Hsp90 inhibitors

ABSTRACT

The invention relates to HSP90 inhibiting compounds consisting of the formula: 
     
       
         
         
             
             
         
       
     
     wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.12/363,640, filed Jan. 30, 2009, which claims priority to U.S.Provisional Application No. 61/025,725, filed Feb. 1, 2008, and U.S.Provisional Application No. 61/101,595, filed Sep. 30, 2008, both ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to inhibitheat shock protein 90 (HSP90) as well as compositions of matter, kitsand articles of manufacture comprising these compounds. The inventionalso relates to methods for inhibiting HSP90 and treatment methods usingcompounds according to the present invention. In addition, the inventionrelates to methods of making the compounds of the present invention, aswell as intermediates useful in such methods. In particular, the presentinvention relates to HSP90 inhibitors, compositions of matter, kits andarticles of manufacture comprising these compounds, methods forinhibiting HSP90, and methods and intermediates useful for making theinhibitors.

BACKGROUND OF THE INVENTION

Molecular chaperones maintain the appropriate folding and conformationof nascent polypeptides. This activity is crucial in regulating thebalance between protein synthesis and degradation. When a protein isdamaged, molecular chaperones may also facilitate their re-folding or,in the case of irreparably impaired proteins, their removal by theprotein degradation machinery of the cell¹

Heat shock proteins (HSPs) were originally defined according to theirincreased expression in response to diverse cellular insults such aselevated temperature as well as exposure to heavy metals and oxidativestress¹. Most, but not all HSPs are molecular chaperones that areorganized into families according to their molecular size or function,including HSP100, HSP90, HSP70, HSP60, HSP40 and small HSPs. The rapidinduction of HSP gene expression is referred to as the heat shockresponse (HSR) which confers cytoprotection to repeat exposure of theinitial insult which would otherwise cause lethal molecular damage².Cytoprotection is an example of increased molecular chaperone expressionassociated with the functioning of normal cells within an organism.However, aberrant expression of this family of proteins can also beassociated with several disease states.

A large body of evidence exists supporting the role of molecularchaperones in maintaining the cancer phenotype. In addition, increasingevidence associating molecular chaperone expression with other diseaseincluding but not limited to: neurodegenerative disorders includingParkinson's, Alzheimer's, Huntington's and prion-related disease,inflammation and inflammation related disorders such as pain, headaches,fever, arthritis, asthma, bronchitis, tendonitis, eczema, inflammatorybowel disease, and the like, and diseases dependent on angiogenesis suchas, cancer, arthritis, diabetic retinopathy, age associated maculardegeneration (AMD) and infectious diseases in particular fungalinfections, viral diseases including but not limited to diseases causedby hepatitis B virus (HBV), hepatitis C virus (HCV) and herpes simplexvirus type-1 (HSV-1), cardiovascular and central nervous systemdiseases^(3,4,5,6,7).

HSP90 is an abundant molecular chaperone which constitutes 1-2% of totalcellular protein. It exerts its chaperone function to ensure the correctconformation, activity, intracellular localization and proteolyticturnover of a range of proteins that are involved in cell growth,differentiation and survival^(3,5,8). Because of the large number ofimportant signaling proteins with which HSP90 has been shown toassociate and assist in stabilizing (these are generally called HSP90client proteins), a rationale exists for the therapeutic use of HSP90inhibitors for the treatment of a wide range of human diseases (asdiscussed above)⁹.

HSP90 activity is required for the stability and the function of manyoncogenic client proteins, which contribute to all of the hallmarktraits of malignancy, and thus, HSP90 has been widely acknowledged as anattractive therapeutic target for the treatment of cancer^(3,4,5,8).These client proteins include: BCR-ABL, AKT/PKB, C-RAF, CDK4, steroidhormone receptors (estrogen and androgen), surviving, c-Met, HER-2, andtelomerases among others. Inhibition of HSP90 function leads to thedestabilization and degradation of client proteins via theubiquitin—proteasome pathway, resulting in the down-regulation ofseveral signals being propagated via oncogenic signaling pathways andmodulation of all aspects of the malignant phenotype^(3,5,8). Therefore,HSP90 inhibitors have potential to treat cancers driven by numerousdiverse molecular abnormalities and their combinatorial effects couldalso reduce the possibility of resistance developing.

HSP90 is considered to exert its chaperone function via a cycle whichutilizes the coordinated interaction of a number of co-chaperoneproteins that are collectively involved in an orchestrated, mutuallyregulatory interplay with ATP/ADP exchange and ATP hydrolysis by theintrinsic and essential N-terminal ATPase domain. Crystallographicstudies have revealed that several HSP90 inhibitors occupy theN-terminus ATP binding site¹⁰, thereby inhibiting HSP90 ATPase activityand function.

The 14-membered macrocyclic antibiotic radicicol was first demonstratedto have anti-tumor activity in vitro and shown to reverse the malignantphenotype of v-SRC transformed cells¹¹. Subsequently, radicicol wasshown using X-ray crystallography to bind to the N-terminal ATP-bindingpocket of HSP90 with high affinity¹⁰, and to inhibit HSP90 ATPaseactivity resulting in the degradation of a number of signalingproteins¹². Although radicicol inhibits tumor cell growth in vitro, itlacks activity in vivo, most likely due to its potentially reactiveepoxide moiety and other adverse chemical features that causeinstability and possible toxicity^(8,13).

The benzoquinone ansamycins are a second class of naturally occurringantibiotics which have been demonstrated to inhibit the activity ofHSP90. The first example is geldanamycin which also competes with ATPfor binding to the N-terminal nucleotide binding site of HSP90¹⁴. As wasthe case with radicicol, despite promising anti-tumor activity in vitro(and in vivo), the development of geldanamycin into a human therapeuticwas stopped due to compound instability and unacceptable hepatotoxicityat therapeutic doses¹⁵.

Analogs of geldanamycin have been pursued with the objective of findingagents with an improved safety margin for clinical use, including thederivative 17-allylamino-17-demethoxygeldanamycin (17-AAG ortanespimycin)¹⁶. 17-AAG has similar cellular effects to geldanamycin,including client protein degradation, and cell cycle arrest but withimproved metabolic stability and lower toxicity^(5,8). Preclinicalstudies using 17-AAG have shown this derivative to be highly potent invitro and to exhibit anti-tumor activity at non-toxic doses in varioushuman tumor xenograft models^(17,18). Based on its biological activity,17-AAG has recently completed several phase I clinical trials with someencouraging results^(9,19). As a result, 17-AAG has now entered phase IImonotherapy clinical trials in various tumor types, including melanomaand breast.

There are several possible factors which may reduce the clinicalefficacy of 17-AAG. Preclinical studies have shown that hepaticmetabolism of 17-AAG by cytochrome P450 leads to the formation of17-amino-17-demethoxygeldanamycin (17-AG)¹⁷. Although 17-AG retainsinhibitory activity, metabolism by CYP3A4 is likely to be a cause ofvariable pharmacokinetics. In addition, the activity of 17-AAG isenhanced by its conversion to the hydroquinone form, 17-AAGH₂, by thereductase enzyme NQO1 or DT-diaphorase^(17,20). The polymorphicexpression of both of these metabolic enzymes may pose limitations forthe clinical use of 17-AAG across the population^(5,8,17). The efficacyof 17-AAG may be further reduced by its association with the multi-drugresistance protein MDR1 or P-glycoprotein¹⁷. Finally, 17-AAG is limitedby its poor solubility, cumbersome and complex formulation and lack oforal bioavailability. Attempts to reformulate 17-AAG have resulted inclinical trials commencing with CNF1010 and a cremaphore-basedformulation (KOS-953) the latter of which has shown promising resultsduring the phase I trial in patients with relapsed-refractory myeloma.The US National Cancer Institute and Kosan Biosciences have alsodeveloped a more water soluble and potentially orally bioavailableanalog of 17-AAG, 17-dimethylaminoethylamino-17-demethoxygeldanamycin(17-DMAG or alvespimycin, which was evaluated in preclinical andclinical trials⁹. 17-AAGH₂, also known as IPI-504, has also enteredclinical trial as a soluble derivative of 17-AAG²¹.

Non-natural product HSP90 inhibitors have recently been described. Oneof these contains a 3,4-diarylpyrazole resorcinol scaffold. Thesemolecules were exemplified by Compound CCT018159, and analoguesCCT0129397/VER-49009 and VER-50589. Treatment of cancer cells with theseHSP90 inhibitors resulted in HSP70 induction, client protein depletion,cytostasis and apoptosis^(22,23,24,25).

Rational drug design was used by Chiosis et al.²⁶ to develop a novelclass of HSP90 inhibitors with a purine-scaffold. The first compound tobe identified from this series, PU3, bound to HSP90 with moderateaffinity resulting in cellular effects which are characteristic of HSP90inhibitors²⁶. An important feature of PU3 is that it is more solublethan 17-AAG; however, it is also significantly less potent against cellsthan the ansamycins²⁶. Subsequent efforts focused on improving thepotency of PU3 and led to the identification of PU24FC1²⁷. This compoundexhibited biological effects on cells within a concentration range of2-6 μM²⁷, and also demonstrated 10-50 times higher affinity for HSP90from transformed cells compared to that from normal tissues²⁷.Administration of PU24FC1 in human breast tumor xenograft models led toanti-tumor activity without significant toxicity²⁷. A more recent studyhas identified 8-arylsulfanyl, 8-arylsulfoxyl and 8-arylsulfonyl adeninederivatives of the PU class which exhibit improved water solubility andapproximately 50 nM potency in cellular models, together withtherapeutic activity in human tumor xenograft models²⁸.

Additional non-natural product small molecule inhibitors of HSP90 havebeen identified including 2-amino-quinazolin-5-one compounds(WO2006113498A2), 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-onecompounds (WO2007041362A1) and quinazolin-oxime derivatives(WO2008142720A2) which target HSP90 for the prophylaxis or treatment ofcell proliferative diseases. These molecules have reasonable potency anddrug-likeness.

The preclinical proof-of-concept provide by small molecules withreasonable drug like properties coupled with the clinicalproof-of-concept for the approach of inhibition of HSP90 activityachieved with 17-AAG, has generated a high level of interest in industryto develop additional HSP90 inhibitors with improved drug likeproperties that can provide therapeutic benefit to patients sufferingfrom disease states related to abnormal protein folding.

The following publications are referred to in the background:

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SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting HSP90. The present invention also provides compositions,articles of manufacture and kits comprising these compounds. Inaddition, the invention relates to methods of making the compounds ofthe present invention, as well as intermediates useful in such methods.

In one aspect, the invention is directed to compounds having theformula:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

A is NR₄ or CR₅R_(5′);

B is CR₇ or N;

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₄ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R_(5′) are each independently selected from the group consistingof hydrogen, cyano, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₇ is selected from the group consisting of hydrogen, cyano, sulfonyl,sulfinyl, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; andprovided that when A is CR₅R_(5′), B is N, X is O, R₁ is (C₁₋₆)alkylsubstituted with at least two hydroxyl groups.

In another aspect, the invention is directed to salts and polymorphs ofthe compounds. Particularly,(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime benzoate Form A.

In another aspect, the invention is directed to pharmaceuticalcompositions that comprise a HSP90 inhibitor according to the presentinvention as an active ingredient. Pharmaceutical compositions accordingto the invention may optionally comprise 0.001%400% of one or moreinhibitors of this invention. These pharmaceutical compositions may beadministered or coadministered by a wide variety of routes, includingfor example, orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery (for example by catheter or stent),subcutaneously, intraadiposally, intraarticularly, or intrathecally. Thecompositions may also be administered or coadministered in slow releasedosage forms.

In another aspect, the invention is directed to kits and other articlesof manufacture for treating disease states associated with HSP90. In oneembodiment, the kit comprises a composition comprising at least oneHSP90 inhibitor of the present invention in combination withinstructions. The instructions may indicate the disease state for whichthe composition is to be administered, storage information, dosinginformation and/or instructions regarding how to administer thecomposition. The kit may also comprise packaging materials. Thepackaging material may comprise a container for housing the composition.The kit may also optionally comprise additional components, such assyringes for administration of the composition. The kit may comprise thecomposition in single or multiple dose forms.

In another aspect, the invention is directed to articles of manufacturethat comprise a composition comprising at least one HSP90 inhibitor ofthe present invention in combination with packaging materials. Thepackaging material may comprise a container for housing the composition.The container may optionally comprise a label indicating the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The article of manufacture may alsooptionally comprise additional components, such as syringes foradministration of the composition. The article of manufacture maycomprise the composition in single or multiple dose forms.

In yet another aspect of the invention is directed to methods forpreparing compounds, compositions, kits, and articles of manufactureaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

In yet other aspect, the invention is directed to methods of usingcompounds, compositions, kits and articles of manufacture according tothe present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit HSP90.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which HSP90 possessactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound is administered to a subject whereinHSP90 activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitsHSP90.

In another embodiment, a method of inhibiting HSP90 is provided thatcomprises contacting a HSP90 with a compound according to the presentinvention.

In another embodiment, a method of inhibiting HSP90 is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit HSP90 in vivo.

In another embodiment, a method of inhibiting a HSP90 is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits HSP90in vivo. It is noted that the compounds of the present invention may bethe first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of treating a condition in a patientthat is known to be mediated by HSP90, or which is known to be treatedby HSP90 inhibitors, comprising administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method is provided for treating a disease statefor which HSP90 possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which HSP90 possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which HSP90 possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby HSP90, or that is known to be treated by HSP90 inhibitors.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula,” “compound having the formula” and “compound of the formula” isintended to encompass the compound and all pharmaceutically acceptableionized forms and solvates, all possible stereoisomers, and all possibleresonance forms and tautomers unless otherwise specifically specified inthe particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting HSP90 and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have HSP90 inhibitory activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates SEQ ID NO:1 and SEQ ID NO: 2 referred to in thisapplication.

FIG. 2 illustrates the powder X-ray diffractogram of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime benzoate Form A.

FIG. 3 shows the differential scanning calorimetry trace and thethermogravimetric trace of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime benzoate Form A.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 5^(TH) ED.” Vols. A (2007) and B(2007), Springer Science+Business Media, New York. Also, unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology, within the skill of the art are employed.

“*” when appears in a chemical structure, particularly in radicals,indicates the point of attachment of the radical.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with (C₃₋₈) rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀) alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms.(C_(X))alkyl and (C_(X-Y))alkyl are typically used where X and Yindicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkyl includes alkyls that have a chain of between 1 and 6 carbons(e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, and thelike). Alkyl represented along with another radical (e.g., as inarylalkyl, heteroarylalkyl and the like) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means a bond (e.g.,(C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl, phenethyl, 1-phenylethyl,3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like). Inparticular embodiments, “alkyl,” either alone or represented along withanother radical, can be a (C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl,a (C₁₋₅)alkyl or a (C₁₋₃)alkyl. Alternatively, “alkyl,” either alone orrepresented along with another radical, can be a (C₁)alkyl, a (C₂)alkylor a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)allynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amido” means the radical —C(═O)—NR—, —C(═O)—NRR′, —NR—C(═O)— and/or—NR—C(═O)R′, wherein each R and R′ are independently hydrogen or afurther substituent.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. Optionally, the twosubstituents together with the nitrogen may also form a ring. Unlessindicated otherwise, the compounds of the invention containing aminomoieties may include protected derivatives thereof. Suitable protectinggroups for amino moieties include acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (C_(X))aryl and (C_(X-Y))aryl are typically used whereX and Y indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with substitutedor unsubstituted nitrogen atoms (—NR— or —NRR′, wherein R and R′ areeach independently hydrogen or further substituents). For example, a(C₁₋₁₀)azaalkyl refers to a chain comprising between 1 and 10 carbonsand one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a (C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₁₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene, a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“EC₅₀” means the molar concentration of an agonist that produces 50% ofthe maximal possible effect of that agonist. The action of the agonistmay be stimulatory or inhibitory.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decaling,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means an alkyl, as defined in this Application, providedthat one or more of the atoms within the alkyl chain is a heteroatom ora carbonyl group. “Heteroalkyl” as defined herein includes alkyl chaincontaining oxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl”),sulfur (See “thioalkyl”), and nitrogen (See “azaalkyl”).Hetero(C_(X))alkyl and hetero(C_(X-Y))alkyl are typically used where Xand Y indicate the number of carbon atoms in the chain. In particularembodiments, “heteroalkyl,” either alone or represented along withanother radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl, ahetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted. In particular embodiments, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N⁺(O⁻)=, —O—, —S— or —S(O)₂—, wherein R is hydrogen or a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloarylor a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S. Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like. In particular embodiments,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkyl, a hetero(C₁₋₉)cycloalkyl, ahetero(C₁₋₆)cycloalkyl, a hetero(C₅₋₉)cycloalkyl or ahetero(C₂₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₄₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Iminoketone derivative” means a derivative comprising the moiety—C(NR)—, wherein R is hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2n⁻¹ enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 5thedition, March, Jerry, John Wiley & Sons, New York, 2001).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Linker” refers to a divalent radical which links together two moieties.A “linker providing X atom separation” between two other moieties meanthat the chain of atoms directly linking the two other moieties is Xatoms in length. When X is given as a range (e.g., X₁-X₂), then thechain of atoms is at least X₁ and not more than X₂ atoms in length. Itis understood that the chain of atoms can be formed from a combinationof atoms including, for example, carbon, nitrogen, sulfur and oxygenatoms. Further, each atom can optionally be bound to one or moresubstituents, as valencies allow. In addition, the chain of atoms canform part of a ring. Accordingly, in one embodiment, a moiety providingX atom separation between two other moieties (R and R′) can berepresented by R-(L)_(X)-R′ where each L is independently selected fromthe group consisting of CR″R′″, NR″″, O, S, CO, CS, C═NR″″, SO, SO₂, andthe like, where any two or more of R″, R′″, R″″ and R″″ can be takentogether to form a substituted or unsubstituted ring.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in P. G. M. Wuts and T. W. Greene, “Greene'sProtecting Groups in Organic Synthesis, 4th edition, John Wiley & Sons,Inc. 2007.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” includes humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

-   (1) preventing the disease from occurring in an animal which may be    predisposed to the disease but does not yet experience or display    the pathology or symptomatology of the disease,-   (2) inhibiting the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    arresting further development of the pathology and/or    symptomatology), or-   (3) ameliorating the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to inhibitHSP90. The present invention also relates to pharmaceuticalcompositions, kits and articles of manufacture comprising suchcompounds. In addition, the present invention relates to methods andintermediates useful for making the compounds. Further, the presentinvention relates to methods of using said compounds. It is noted thatthe compounds of the present invention may also possess activity forother members of the same protein family and thus may be used to addressdisease states associated with these other family members.

It is noted that the compounds of the present invention may also possessinhibitory activity for other HSP family members and thus may be used toaddress disease states associated with these other family members.

Compound of the Invention

In one of its aspects, the present invention relates to compounds thatare useful as HSP90 inhibitors. In one embodiment, HSP90 inhibitors ofthe present invention is of a formula selected from the group consistingof:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₄ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R_(5′) are each independently selected from the group consistingof hydrogen, cyano, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₇ is selected from the group consisting of hydrogen, cyano, sulfonyl,sulfinyl, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

provided that for Formula II, when X is O, R₁ is a (C₁₋₆)allylsubstituted with at least two hydroxyl group.

In another embodiment, the compounds of the invention consisting theformula:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₅ and R_(5′) are each independently selected from the group consistingof hydrogen, cyano, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl,sulfinyl, (C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₇ is selected from the group consisting of hydrogen, cyano, sulfonyl,sulfinyl, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the compounds of the invention consist of theformula

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)allylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₅ and R_(5′) are each independently selected from the group consistingof hydrogen, cyano, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

provided that when X is O, R₁ is (C₁₋₆)allyl, substituted with at leasttwo hydroxyl groups.

In one embodiment, the compounds of the invention having the formula:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)allylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₄ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₇ is selected from the group consisting of hydrogen, cyano, sulfonyl,sulfinyl, (C₁₋₁₀)allyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, eachsubstituted or unsubstituted;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the compounds of the invention consisting of theformula:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxyhetero(C₁₋₁₀) aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₄ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the compounds of the invention consisting of theformula:

or a tautomer, stereoisomer, or pharmaceutically acceptable saltthereof, wherein

X is O, NR₈ or CR₉R_(9′);

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)allylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted;

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, halo, nitro,cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,(C₁₋₁₀)alkenyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with 1-3 substituents, and the substituents on adjacentatoms may be taken together to form a substituted or unsubstituted ring;

R₄ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₆ and R_(6′) are each independently selected from the group consistingof hydrogen, halogen, cyano, (C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, providedthat R_(6′) is absent when A is CR₅R₅;

R₈ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ and R_(9′) are each independently selected from the group consistingof hydrogen, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

X

In one variation of the above embodiments of the compounds of theinvention, X is O.

In another variation, X is NR₈, where R₈ is selected from the groupconsisting of hydrogen, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, each substituted or unsubstituted.

In yet another variation, X is NR₈ where R₈ is selected from the groupconsisting of hydrogen, hydroxylalkyl, alkyl, aminoalkyl, andalkoxyalkyl.

In still another variation, X is NR₈ where R₈ is selected from the groupconsisting of hydrogen, hydroxyl, (C₁₋₃)alkyl, and hydroxy(C₁₋₃)alkyl.

In still another variation, X is NH.

In still another variation, X is CR₉R_(9′) where R₉ and R_(9′) are eachindividually selected from the group consisting of hydrogen,(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, eachsubstituted or unsubstituted.

In still another variation, X is CR₉R_(9′) where R₉ and R_(9′) are eachindependently selected from the group consisting of hydrogen, hydroxyl,halo, (C₁₋₃)alkyl, hydroxy(C₁₋₃)alkyl, (C₁₋₃)alkoxy, amino, aryl andheteroaryl.

In still another variation, X is CR₉R_(9′) where one of R₉ and R_(9′) isindependently hydrogen.

In still another variation, X is CH₂.

R₁

In one variation of the above embodiments and variations of thecompounds of the invention, R₁ is selected from the group consisting ofhydrogen, carbonyl, hydroxycarbonyl, oxycarbonyl, aminocarbonyl,sulfonyl, sulfinyl, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hetero(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl,imino(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, sulfonyl(C₁₋₆)alkyl,sulfinyl(C₁₋₆)alkyl, carbonylamino(C₁₋₆)alkyl, thiocarbonyl(C₁₋₆)alkyl,hydroxylcarbonyl(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl,aminosulfonyl(C₁₋₆)alkyl, sulfonylamino(C₁₋₆)alkyl,(C₁₋₆)alkylsulfonylamino(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,hetero(C₃₋₅)cycloalkyl(C₁₋₆)alkyl, (C₄₋₆)aryl(C₁₋₆)alkyl, andhetero(C₁₋₅)aryl(C₁₋₆)alkyl, each unsubstituted or substituted.

In another variation, R₁ is selected from the group consisting ofhydrogen, hydroxycarbonyl, oxycarbonyl, aminocarbonyl, (C₁₋₆)alkyl,halo(C₁₋₆)alkyl, hetero(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl,alkoxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, imino(C₁₋₆)alkyl,carbonyl(C₁₋₆)alkyl, carbonylamino(C₁₋₆)alkyl, thiocarbonyl(C₁₋₆)alkyl,hydroxylcarbonyl(C₁₋₆)alkyl, aminocarbonyl(C₁₋₆)alkyl,(C₁₋₆)alkylamino(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,hetero(C₃₋₅)cycloalkyl(C₁₋₆)alkyl, (C₄₋₆)aryl(C₁₋₆)alkyl, andhetero(C₁₋₅)aryl(C₁₋₆)alkyl, each unsubstituted or substituted.

In another variation, R₁ is selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hetero(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, alkoxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl,carbonylamino(C₁₋₆)alkyl, hydroxylcarbonyl(C₁₋₆)alkyl,aminocarbonyl(C₁₋₆)alkyl, (C₁₋₆)alkylamino(C₁₋₆)alkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, hetero(C₃₋₅)cycloalkyl(C₁₋₆)alkyl,(C₄₋₆)aryl(C₁₋₆)alkyl, and hetero(C₁₋₅)aryl(C₁₋₆)alkyl, eachunsubstituted or substituted.

In one particular variation of the above embodiments and variations ofthe compounds of the invention, R₁ is -L-R₄₅, where L is absent or is alinker of one to five atoms, wherein the atoms in L are eachindependently selected from the group consisting of N, O, and S, and areindependently unsubstituted or substituted with 1-2 substituentsselected from the group consisting of nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, oxo,carbonyl, oxycarbonyl, aminocarbonyl, amino, alkylcarbonylamino,(C₁₋₁₀)alkylamino, sulfonylamino, aminosulfonyl, sulfonyl, sulfinyl,imino, (C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₆)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,heteraryl(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryland heteroaryl, each unsubstituted or further substituted; or any twosubstituents on adjacent atoms of L are taken to form a 3, 4 and 5membered ring, each unsubstituted or substituted; and

R₄₅ is independently selected from the group consisting of hydrogen,hydroxyl, halo, (C₁₋₃)alkyl, hydroxy(C₁₋₃)alkyl, (C₁₋₃)alkoxy, amino,carbonylamino, aminocarbonyl, carbonyl, hydroxylcarbonyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each unsubstituted orfurther substituted.

In some variations L is absent.

In some variations of the above particular variation, L is an alkyl orheteroalkyl of one to five atoms where each atom is independentlyselected from the group consisting of N and O, and each atoms isindependently unsubstituted or substituted with 1-2 substituentsselected from the group consisting of hydroxy, oxo, carbonyloxy,(C₁₋₆)alkoxy, (C₄₋₆)aryloxy, hetero(C₁₋₅)aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, alkylcarbonylamino, (C₁₋₁₀)alkylamino, imino,(C₁₋₆)alkyl, hetero(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl,thiocarbonyl(C₁₋₆)alkyl, sulfonyl(C₁₋₆)alkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, hetero(C₃₋₆)cycloalkyl(C₁₋₆)alkyl,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,hetero(C₃₋₆)cycloalkyl, aryl and heteroaryl, each unsubstituted orfurther substituted.

In other variation, L is (—CR₄₆R₄₇—)_(n), where n is 1, 2, 3, 4, or 5.In yet other variations, L is (—CR₄₆R₄₇—)₅. In still other variations, Lis (—CR₄₆R₄₇—)₄. In still other variations, L is (—CR₄₆R₄₇—)₃. In stillother variations, L is (—CR₄₆R₄₇—)₂. In still other variations, L is—(CR₄₆R₄₇)—.

In the above variations where L is (—CR, RA)_(n), R₄₆ and R₄₇ are eachindependently selected from the group consisting of hydrogen, hydroxy,oxo, carbonyloxy, (C₁₋₆)alkoxy, (C₄₋₆)aryloxy, hetero(C₁₋₅)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, alkylcarbonylamino,(C₁₋₁₀)alkylamino, imino, (C₁₋₆)alkyl, hetero(C₁₋₆)alkyl,hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl, thiocarbonyl(C₁₋₆)alkyl,sulfonyl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,hetero(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl, hetero(C₃₋₆)cycloalkyl, aryland heteroaryl, each unsubstituted or further substituted.

In other variations, R₄₆ and R₄₇ are each independently selected fromthe group consisting of hydrogen, hydroxyl, hydroxy(C₁₋₆)alkyl,(C₁₋₆)alkoxy, oxo, amino, imino, (C₁₋₆)alkyl, (C₄₋₆)aryl(C₁₋₆)alkyl,hetero(C₁₋₅)aryl(C₁₋₆)alkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₆)alkyl, (C₄₋₆)aryl, hetero(C₁₋₅)aryl,(C₃₋₆)cycloalkyl, and hetero(C₁₋₅)cycloalkyl, each unsubstituted orsubstituted. In other variations, R₄₆ and R₄₇ are each independentlyselected from the group consisting of hydrogen, hydroxyl, oxo,(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy, amino and aminocarbonyl,each substituted or unsubstituted. In other variations, R₄₆ and R₄₇ areboth hydrogen.

In one variation of the above embodiment and variations, R₁ is selectedfrom the group consisting of hydrogen, and

In another variation, R₁ is selected from the group consisting ofhydrogen,

In still another variation, R₁ is selected from the group consisting ofhydrogen,

In still another variation, R₁ is selected from the group consisting ofhydrogen,

In still another variation, R₁ is selected from the group consisting ofhydrogen,

In still other variations, R1 is selected from the group consisting ofhydrogen,

In yet other variations, R₁ is

In yet other variations, R₁ is

In yet other variations, R₁ is

In yet other variations, R₁ is

In still further variations, R₁ is

In yet further variations, R₁ is

In yet further variations, R₁ is

In still yet further variations, R₁ is hydrogen

X—R₁

In one variation of the above embodiments and variations of thecompounds of the invention, —X—R₁ is selected from the group consistingof

In another variation, —X—R₁ is selected from the group consisting of

In another variation, —X—R₁ is selected from the group consisting of

In another variation, —X—R₁ is selected from the group consisting ofhydroxyl, methoxy,

In still other variations, —X—R₁ is —OH. In still other variations,—X—R₁ is —OCH₃. In still other variations, —X—R₁ is

In still other variations, —X—R₁ is

In still further variations, —X—R₁ is

In still further variations, —X—R₁ is

In other further variations, —X—R₁ is

In yet other further variations, —X—R₁ is

In other further variations, —X—R₁ is

In yet other further variations, —X—R₁ is

R₂

In another variation of the embodiments and variations of the compoundsof the invention, R₂ is selected from the group consisting of hydrogen,halo, hydroxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another variation, R₂ is selected from the group consisting ofhydrogen, of hydrogen, hydroxyl, halo, cyano, thiol, (C₁₋₆)alkoxy,(C₁₋₆)alkylthiol, (C₁₋₆)alkyl, hetero(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, (C₁₋₅)cycloalkyl(C₁₋₆)alkyl,hetero(C₁₋₅)cycloalkyl(C₁₋₆)alkyl, (C₄₋₆) aryl, (C₁₋₅) heteroaryl,(C₁₋₆)cycloalkyl, and hetero(C₁₋₅)cycloalkyl, each unsubstituted andsubstituted.

In yet another variation, R₂ is selected from the group consisting ofhydrogen, hydroxyl, halo, cyano, thiol, (C₁₋₆)alkoxy, (C₁₋₆)alkylthiol,(C₁₋₆)alkyl, hetero(C₁₋₆)alkyl, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl,(C₁₋₅)cycloalkyl(C₁₋₆)alkyl, hetero(C₁₋₅)cycloalkyl(C₁₋₆)alkyl, (C₄₋₆)aryl, (C₁₋₅) heteroaryl, (C₁₋₆)cycloalkyl, and hetero(C₁₋₅)cycloalkyl,each unsubstituted and substituted.

In yet another variation, R₂ is selected from the group consisting ofhydrogen, hydroxyl, methyl, ethyl, methoxymethyl, trifluoromethyl,phenylethyl, and substituted benzyl where the substituents are eachindependently selected from the group consisting of methoxy, halo,nitro, amino, and acetamide.

In still another variation, R₂ is selected from the group consisting ofhydrogen, (C₁₋₆)alkyl or halo(C₁₋₆)alkyl, aza(C₁₋₆)alkyl,(C₁₋₆)oxaalkyl, each unsubstituted or substituted.

In yet another variation, R₂ is selected from the group consisting ofunsubstituted or substituted (C₁₋₆)alkyl.

In yet another variation, R₂ is hydrogen.

In yet another variation, R₂ is methyl.

R₄

In one variation of the above embodiments and variations of thecompounds of the invention, when present, R₄ is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl, and hetero(C₃₋₁₂)cycloalkyl, eachunsubstituted or substituted.

In another variation, when present, R₄ is selected from the groupconsisting of hydrogen, methyl, ethyl, allyl, 3-methylbutyl, isobutyl,2-hydroxyethyl, 3-aminopropyl, 1-(4-methoxyphenyl)ethyl,(2-methyl-2-morpholin-4-yl)propyl, pyridin-4-ylmethyl,tetrahydropyran-4-ylmethyl, benzyl, 2,4-dimethoxy-benzyl,3-chloro-benzyl, 2-chloro-benzyl, 2-fluoro-benzyl, 4-fluoro-benzyl,3-trifluoromethyl-benzyl, pyrazin-2-yl, and—(CH₂)₃NHC(O)O—C(CH₃)₃.

In yet another variation, when present, R₄ is selected from the groupconsisting of hydrogen, unsubstituted (C₁₋₆)alkyl, and substituted(C₁₋₆)alkyl.

In yet another variation, when present, R₄ is selected from the groupconsisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl.

In still another variation, when present, R₄ is selected from the groupconsisting of hydrogen, benzyl, 1-(4-methoxyphenyl)ethyl,1-methyl-(4-methoxyphenyl)methyl, methyl, 3-aminopropyl, and2-methyl-2-morpholinopropyl.

In still another variation, when present, wherein R₄ is hydrogen.

R₅ and R_(5′)

In one variation of the embodiments and variations of the compounds ofthe invention, when present, R₅ and R_(5′) are each independentlyselected from the group consisting of hydrogen, halo, cyano, carbonyl,aminocarbonyl, sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, and hetero(C₁₋₁₀)alkyl, eachsubstituted or unsubstituted.

In another variation, when present, R₅ and R_(5′) are each independentlyselected from the group consisting of hydrogen, halogen, (C₁₋₆)alkyl,—OR₄₂, —SR₄₂, —N(R₄₂)₂, —OC(O)R₄₂, —NR₄₂C(O)R₄₂, and —N(R₄₂)S(O)₂R₄₂,where R₄₂ is selected from the group consisting of hydrogen,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl,(C₅₋₇)cycloalkenyl, aryl, heteroaryl, and (C₃₋₇)heterocycloalkyl, eachunsubstituted or substituted.

In another variation, when present, R₅ and R_(5′) are each independentlyselected from the group consisting of hydrogen, unsubstituted(C₁₋₆)alkyl, and substituted (C₁₋₆)alkyl.

In still another variation, when present, R₅ and R_(5′) is hydrogen.

In yet another variation, when present, both R₅ and R_(5′) are hydrogen.

R₆

In one variation of the embodiments and variations of the compounds ofthe invention, when present, R₆ and R_(6′) are each independentlyselected from the group consisting of hydrogen, halogen, cyano,(C₁₋₁₀)alkyl, and hetero(C₁₋₁₀)alkyl, each substituted or unsubstituted.

In another variation, when present, R₆ and R_(6′) are each independentlyselected from the group consisting of hydrogen, halogen, cyano,(C₁₋₆)alkyl, —OR₄₃, —SR₄₃, —N(R₄₃)₂, —OC(O)R₄₃, —NR₄₃C(O)R₄₃, and—N(R₄₃)S(O)₂R₄₃, where R₄₃ is selected from the group consisting ofhydrogen, halogen, cyano, nitro, amino, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₂₋₆)alkynyl, (C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl, aryl, heteroaryl,and (C₃₋₇)heterocycloalkyl, each unsubstituted or substituted.

In still another variation, when present, R₆ and R_(6′) are eachindependently selected from the group consisting of hydrogen, halogen,unsubstituted or substituted (C₁₋₆)alkyl.

In still another variation, when present, R₆ and R_(6′) are bothhalogen.

In still another variation, when present, one of R₆ and R_(6′) ishalogen, and the other one of R₆ and R_(6′) is hydrogen.

In one variation, the halogen of the R₆ and R_(6′) definition is fluoro.

In yet still other variations, when present, R₆ and R_(6′) are bothhydrogen.

In yet still other variations, when present, R₆ is fluoro. In yet stillother variations, when present, R₆ is cyano. In yet another variation,when present, R₆ is hydrogen.

R₇

In one variation of the embodiments and variations of the compounds ofthe invention, when present, R₇ is selected from the group consisting ofhydrogen, cyano, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,amino(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,(C₁₋₁₀)alkoxy, and (C₁₋₁₀)alkoxy(C₁₋₁₀)alkyl, each unsubstituted orsubstituted.

In another variation, when present, R₇ is selected from the groupconsisting of hydrogen, cyano, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, and (C₁₋₁₀)oxaalkyl, eachsubstituted or unsubstituted.

In another variation, when present, R₇ is selected from the groupconsisting of hydrogen, cyano, alkoxy, hydroxylalkyl, alkyl, aminoalkyl,and alkoxyalkyl.

In yet another variation, when present, R₇ is hydrogen.

R₃

In one variation of the above embodiments and variations of thecompounds of the invention, R₃ is selected from the group consisting ofhydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₃₋₁₅)cycloalkyl,hetero(C₁₋₁₄)cycloalkyl cycloalkenyl, (C₄₋₁₅)aryl, andhetero(C₁₋₁₄)aryl, each unsubstituted or substituted with 1-4substituents each of which is independently selected from the groupconsisting of hydrogen, halo, cyano, thio, oxy, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonylamino,aminosulfonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₄₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each unsubstituted or substituted with 1-3substituents, or the substituents on adjacent atom may be taken togetherto form a substituted or unsubstituted ring.

In one variation, R₃ is of the formula

wherein

R₁₀ and R₁₁ are each independently selected from the group consisting ofhydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted, or R₁₀ and R₁₁ are taken together to form Ring C which isselected from a group consisting of monocyclic, bicyclic, saturated,unsaturated, aromatic, carbocyclyl and heterocyclyl, each unsubstitutedor substituted with 1-3 substituents independently selected from thegroup consisting of hydroxy, nitro, halo, cyano, thio, oxy, carbonyloxy,(C₁₋₁₀)alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonylamino, aminosulfonyl,sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted; and

R₁₂ is selected from a group consisting of C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,(C₃₋₁₂)cycloalkyl, and hetero(C₂₋₁₁)cycloalkyl, each unsubstituted orsubstituted with 1-3 substituents independently selected from the groupconsisting of hydroxy, halo, nitro, cyano, thio, alkylthio, carbonyloxy,(C₁₋₁₀)alkoxy, (C₁₋₁₀)haloalkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, alkylaminocarbonyl, amino, amido,(C₁₋₁₀)alkylamino, sulfonylamino, aminosulfonyl, imino, alkoxyalkyl,alkoxycarbonylalkyl, aryloxyalkyl, heteroarylalkyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, unsubstituted orsubstituted; or one of said 1-3 substituents on R₁₂ and one of said 1-3substituents on said Ring C are taken together to form a six or sevenmembered, saturated, unsaturated, or aromatic ring that is unsubstitutedor substituted with 1-4 substituents.

In one variation, when present, R₁₀ is selected from the groupconsisting of hydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl, andhetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, each substituted or unsubstituted.

In another variation, when present, R₁₀ is selected from the groupconsisting of hydrogen, halo, unsubstituted or substituted alkyl, andunsubstituted or substituted heteroalkyl.

In still another variation, when present, R₁₀ is selected from the groupconsisting of hydrogen, halo, unsubstituted or substituted alkyl.

In one variation, when present, R₁₁ is selected from the groupconsisting of hydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl, andhetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, each substituted or unsubstituted.

In another variation, when present, R₁₁ is selected from the groupconsisting of hydrogen, halo, alkyl, and heteroalkyl.

In still another variation, when present, R₁₁ is methyl.

R₁₀ and R₁₁ are Taken Together to Form a Ring

In one specific variation of R₃, where R₁₀ and R₁₁ are taken together toform Ring C, R₃ is of the formula

wherein Ring C is selected from the group consisting of (C₄₋₁₂)aryl,(C₁₋₁₁)heteroaryl, (C₃₋₁₂)cycloalkyl, and hetero(C₁₋₁₁)cycloalkyl, eachof which is unsubstituted or substituted said 1-3 substituentsindependently selected from the group consisting of hydroxy, nitro,halo, cyano, thio, oxy, carbonyloxy, (C₁₋₁₀)alkoxy, aryloxy,heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonylamino, aminosulfonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In another variation, Ring C is selected from the group consisting ofaryl, heterocyclyl, heteroaryl, (C₃₋₇)cycloalkyl, and(C₅₋₇)cycloalkenyl, each of which is substituted with 1-3 substituents.In some variations, the aryl, heterocyclyl, heteroaryl,(C₃₋₇)cycloalkyl, and (C₅₋₇)cycloalkenyl is selected from the groupconsisting of pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole,thiadiazole, furanyl, quinolinyl, isoquinolinyl, isoxazolyl, oxazolyl,thiazolyl, morpholino, piperidinyl, pyrrolidinyl, thienyl, cyclohexyl,cyclopentyl, cyclohexenyl, and cyclopentenyl, each unsubstituted orsubstituted with 1-3 substituents selected from the group consisting ofhalo, alkoxy, alkyl, amino, alkylamino, haloalkyl, and haloalkoxy.

In another variation, Ring C is selected from the group consisting of(C₄₋₆)aryl or (C₁₋₅)heteroaryl, each unsubstituted or substituted with1-3 substituents. In one variation, the aryl or heteroaryl is selectedfrom the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, thiazolyl, and thienyl, each of which is unsubstituted orsubstituted with 1-3 substituents.

In the above embodiments and variations, the 1-3 substituents on Ring Cis, in some variations, independently selected from the group consistingof hydroxy, nitro, halo, cyano, thio, oxy, carbonyloxy, (C₁₋₁₀)alkoxy,aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonylamino, aminosulfonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted. In some other variations, the 1-3 substituents are eachindependently selected from the group consisting of substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, halo,alkyl, haloalkyl, alkoxy, and haloalkoxy. In some other variations, atleast one of the 1-3 substituents on Ring C is selected from the groupconsisting of fluoro, methyl, and methoxy. In other variations, the 1-3substituents on Ring C are each independently selected from the groupconsisting of halo. In other variations, the substituents are fluoro. Instill other variations, the substituents are methyl. In yet still othervariations, the substituents are methoxy.

In one particular variation, R₃ is of the formula:

wherein

J₁₀ is selected from the group consisting of O, S, NR₂₆, andCR₂₇R_(27′),

J₁₁ is selected from the group consisting of O, S, NR₂₈, andCR₂₉R_(29′),

J₁₂ is selected from the group consisting of O, S, NR₃₀, and CR₃₁R_(3y),

-   -   where        -   R₂₆, R₂₈ and R₃₀ are each independently selected from the            group consisting of hydrogen, (C₁₋₁₀)alkylamino,            sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,            halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,            thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,            sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)allyl, imino(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,            (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,            hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and            hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,            or R₂₆, R₂₈, and R₃₀ are each independently absent when the            nitrogen atom to which it is bound forms parts of a double            bond, and        -   R₂₇, R_(27′), R₂₉, R_(29′), R₃₁, and R_(31′) are each            independently selected from the group consisting of            hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,            carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,            hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,            amino, (Cl_(—)10)alkylamino, sulfonamido, sulfonyl,            sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,            thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,            sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, or R_(22′), R_(29′), R_(31′)            are each independently absent when the carbon atom to which            it is bound forms parts of a double bond.

In one variation of the above variation of Ring C, R₂₆, R₂₈ and R₃₀, areeach individually selected from the group consisting of hydrogen,(C₁₋₁₀)allylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)allyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl, andhetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, each substituted or unsubstituted, or R₂₆,R₂₈, and R₃₀ are each independently absent when the nitrogen to which itis bound forms parts of a double bond; and R₂₇, R_(22′), R₂₉, R_(29′),R₃₁, and R_(31′) are each individually selected from the groupconsisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, each substituted or unsubstituted, orR_(22′), R_(29′), R_(31′) are each independently absent when the carbonatom to which it is bound forms parts of a double bond.

In yet another variation of the above embodiment of Ring C, R₂₆, R₂₈ andR₃₀, are each individually selected from the group consisting ofhydrogen, (C₁₋₁₀)alkylamino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, and aza(C₁₋₁₀)alkyl, eachsubstituted or unsubstituted, or R₂₆, R₂₈, and R₃₀ each is independentlyabsent when the nitrogen atom to which it is bound forms parts of adouble bond; and R₂₇, R_(27′), R₂₉, R_(29′), R₃₁, and R_(31′) are eachindividually selected from the group consisting of hydrogen, halo,nitro, cyano, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, carbonyl,aminocarbonyl, amino, (C₁₋₁₀)alkylamino, hydroxy(C₁₋₁₀)alkyl,aza(C₁₋₁₀)allyl, and (C₁₋₁₀)oxaalkyl, each substituted or unsubstituted,or R_(27′), R_(29′), R_(31′) are each independently absent when thecarbon atom to which it is bound forms parts of a double bond.

In still another variation, R₂₆, R₂₈ and R₃₀, are each individuallyselected from the group consisting of hydrogen, (C₁₋₆)allylamino,(C₁₋₆)allyl, halo(C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, carbonyl(C₁₋₆)alkyl,aza(C₁₋₆)allyl, each substituted or unsubstituted, or R₂₆, R₂₈, and R₃₀each is independently absent when the nitrogen atom to which it is boundforms part of a double bond; and R₂₇, R_(27′), R₂₉, R_(29′), R₃₁, andR_(31′) are each individually selected from the group consisting ofhydrogen, halo, nitro, cyano, oxy, hydroxy, carbonyloxy, (C₁₋₆)alkoxy,carbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino, hydroxy(C₁₋₁₀)alkyl,aza(C₁₋₆)alkyl, (C₁₋₆)oxaalkyl, each substituted or unsubstituted, orR_(27′), R_(29′), R_(31′) are each independently absent when the carbonatom to which it is bound forms part of a double bond.

In another particular variation, R₃ is of the formula:

where

J₁₃ is selected from the group consisting of O, S, NR₃₂, andCR₃₃R_(33′),

J₁₄ is selected from the group consisting of O, S, NR₃₄, andCR₃₅R_(35′),

J₁₅ is selected from the group consisting of O, S, NR₃₆, andCR₃₂R_(37′),

J₁₆ is selected from the group consisting of O, S, NR₃₈, andCR₃₉R_(39′,)

-   -   where        -   R₃₂, R₃₄, R₃₆, and R₃₈ are each independently selected from            the group consisting of hydrogen, oxy, hydroxy,            (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,            (C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,            carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,            sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)allyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,            (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,            hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and            hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,            or R₃₂, R₃₄, R₃₆, and R₃₈ are each independently absent when            the nitrogen atom to which it is bound forms parts of a            double bond, and        -   R₃₃, R_(33′), R₃₅, R_(35′), R₃₇, R_(37′), R₃₈, and R₃₈, are            each independently selected from the group consisting of            hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,            carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,            hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,            amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,            (C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,            carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,            sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, or R_(33′), R_(35′), R_(37′),            and R_(39′) are each independently absent when the carbon            atom to which it is bound forms parts of a double bond, and

R₁₂ is as previously defined.

In one variation of the above embodiment of Ring C, R₃₂, R₃₄, R₃₆, andR₃₈ are each independently selected from the group consisting ofhydrogen, oxy, hydroxy, (C₁₋₁₀)alkylamino, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, each substituted or unsubstituted, or R₃₂,R₃₄, R₃₆, and R₃₈ are each independently absent when the nitrogen atomto which it is bound forms parts of a double bond, and R₃₃, R_(33′),R₃₅, R_(35′), R₃₇, R_(37′), R₃₉, and R_(39′) are each independentlyselected from the group consisting of hydrogen, halo, nitro, cyano,thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, each substituted orunsubstituted, or R_(33′), R_(35′), R_(37′), and R_(39′) are eachindependently absent when the carbon atom to which it is bound formsparts of a double bond.

In still another variation, R₃₂, R₃₄, R₃₆, and R₃₈ are eachindependently selected from the group consisting of hydrogen, oxy,hydroxy, (C₁₋₁₀)alkylamino, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, each substituted or unsubstituted, or R₃₂, R₃₄, R₃₆,and R₃₈ are each independently absent when the nitrogen atom to which itis bound forms parts of a double bond, and R₃₃, R_(33′), R₃₅, R_(35′),R₃₇, R_(37′), R₃₉, and R_(39′) are each independently selected from thegroup consisting of hydrogen, halo, nitro, cyano, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, aminocarbonyl, amino, (C₁₋₁₀)allylamino,(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,aza(C₁₋₁₀)alkyl, (C₁₋₁₀)oxaalkyl, each substituted or unsubstituted, orR_(33′), R_(35′), R_(37′), and R_(39′) are each independently absentwhen the carbon atom to which it is bound forms parts of a double bond.

In still another variation, R₃ is selected from the group consisting of

where

R₂₉ and R₃₁ are each independently selected from the group consisting ofhydrogen, halo, cyano, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,(C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, each substituted or unsubstituted;

R₃₃, R₃₅, R₃₇, and R₃₉ are each independently selected from the groupconsisting of hydrogen, halo, (C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl; and

R₃₄ and R₃₆ are each independently selected from selected from the groupconsisting of alkyl, aza(C₁₋₁₀)alkyl, and hydroxyl(C₁₋₁₀)alkyl.

In still another variation, wherein R₃ is of the formula

where

R₂₉ and R₃₁ are each independently selected from the group consisting ofhydrogen, halogen, cyano, nitro, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₂₋₆)alkynyl, amino or substituted amino, aryl, heteroaryl,(C₃₋₇)cycloalkyl, (C₅₋₇)cycloalkenyl, (C₃₋₇)heterocycloalkyl, —OR₄₀,—SR₄₀, —C(O)R₄₀, —C(O)OR₄₀, —C(O)N(R₄₀)₂, —S(O)R₄₀, —S(O)₂R₄₀,—S(O)₂N(R₄₀)₂, —OC(O)R₄₀, —NR₄₀C(O)R₄₀, and —N(R₄₀)S(O)₂R₄₀;

-   -   where        -   R₄₀ is selected from the group consisting of methyl, ethyl,            isopropyl, cyclopentyl, cyclohexyl, unsubstituted or            substituted phenyl, unsubstituted or substituted thiazolyl,            unsubstituted or substituted pyridyl, unsubstituted or            substituted pyrazinyl, and unsubstituted or substituted            pyrimindinyl, 2-aminoethyl, 2-piperidinylethyl,            2-piperazinylethyl, 2-morpholinylethyl, and            2-(N-methylpiperazinyl)ethyl.

In one variation of the immediately above variation, R₄₀ is selectedfrom the group consisting of methyl, ethyl, isopropyl, cyclopentyl, and2-aminoethyl. In another variation, R₄₀ is methyl. In another variation,R₄₀ is ethyl. In another variation, R₄₀ is isopropyl. In anothervariation, R₄₀ is cylcopentyl. In another variation, R₄₀ is2-aminoethyl.

In still another variation, R₃ is of the formula

where

R₃₃, R₃₅, R₃₇, and R₃₉ are each independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halo, unsubstituted orsubstituted aryl, and substituted heteroaryl.

In still another variation, R₃ is selected is selected from the groupconsisting of

R₁₂

Of the above embodiments and variations of the present invention, insome variations, R₁₂ is selected from the group consisting of(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, (C₃₋₁₂)cycloalkyl, andhetero(C₂₋₁₁)cycloalkyl, each unsubstituted or substituted with 1-3substituents. In other variations R₁₂ is selected from the groupconsisting of furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,indolyl, isoindolyl, indolizinyl, benzimidazolyl, purinyl, naphthalenyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinlyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, pyridone, and pyrimidone, eachof which is unsubstituted or substituted with 1-3 substituents.

In some variations of the above embodiments and variations, the 1-3substituents of R₁₂ are each independently selected from the groupconsisting of halo, nitro, cyano, thio, oxy, oxo, hydroxy, carbonyloxy,(C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl,oxycarbonyl, aminocarbonyl, amino, amido, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each unsubstituted or further substituted.

In other variations, the 1-3 substituents on R₁₂ are each independentlyselected from the group consisting of halo, cyano, oxy, oxo,(C₁₋₆)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀) aryloxy, carbonyl, amino,amido, sulfonyl, (C₁₋₆)allyl, sulfonyl(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)allyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, hetero(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, andhetero(C₁₋₁₀)aryl, each unsubstituted or substituted.

In still other variations, the 1-3 substituents on R₁₂ are eachindependently selected from the group consisting of halo, cyano,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, amino, acetamido, carbonyl, aryl, heteroaryl,cycloalkyl, and heterocycloalkyl, each unsubstituted or substituted. Instill other variations, the 1-3 substituents on R₁₂ are eachindependently selected from the group consisting of fluoro, difluoro,chloro, bromo, cyano, amino, methylamino, ethylamino dimethylamino,hydroxyethylamino, methyl, ethyl, ethynyl, trifluoromethyl, aminomethyl,methoxy, ethoxy, dimethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy,phenoxy, acetamido, ethoxyacetamido, acetyl, substitutedmethoxycarbonyl, ethoxyaminocarbonyl, methanesulfonylamino,4-trifluoromethoxyphenoxymethyl, 3-trifluoromethoxyphenoxymethyl, andisothiazolidine 1,1 dioxide. In still other variations, the 1-3substituents on R₁₂ are each independently selected from the groupconsisting of fluoro, chloro, methoxy, ethoxy, and amino In stillanother variation, the 1-3 substituents on R₁₂ are each independentlyselected from the group consisting of fluoro, chloromethoxy, ethoxy, andamino

In still another variation, R₁₂ is selected from the group consisting of(2-hydroxy-ethylamino)-pyrazin-2-yl, 1H-pyrazol-4-yl,1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-pyrazol-4-yl,2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl,2,3-dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl,2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl,2,6-dimethyl-pyridin-3-yl, 2-acetamidophenyl, 2-aminocarbonylphenyl,2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl,2-chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl,2-chloro-pyridin-4-yl, 2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl,2-ethoxy-thiazol-4-yl, 2-fluoro-3-methoxy-phenyl,2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl,2-fluoro-5-methoxy-phenyl, 2-fluoro-5-methylphenyl, 2-fluorophenyl,2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-methoxyphenyl,2-hydroxymethylphenyl, 2-isoquinolin-4-yl,2-methoxy-5-trifluoromethyl-phenyl, 2-methoxy-phenyl,2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl,2-methoxy-thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl,2-oxo-1,2-dihydro-pyridin-3-yl, 2-phenoxyphenyl, 2-pyridin-3-yl,2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-trifluoromethoxy-phenyl,3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl,3,6-dimethyl-pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl,3-bromo-phenyl, 3-chloro-pyrazin-2-yl, 3-cyanophenyl,3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-phenyl,3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl,3-fluoro-pyrazin-2-yl, 3-methanesulfonamidophenyl,3-methoxycarbonylphenyl, 3-methoxyphenyl, 3-methoxy-pyrazin-2-yl,3-methyl-3H-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl,3-methyl-pyridin-2-yl, 3-trifluoromethoxyphenyl,3-trifluoromethylphenyl, 4,5-dimethoxy-pyrimidin-2-yl,4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl,4-chloro-2-fluoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl,4-chloro-pyridin-3-yl, 4-difluoro-2-methyl-phenyl,4-ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-pyrazol-3-yl,4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-phenyl, 4-fluorophenyl,4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl,4-methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl,4-methyl-pyridin-2-yl, 4-methyl-pyridin-3-yl,4-pyrrolidin-1-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl,5-acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl,5-amino-6-methoxy-3-methyl-pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl,5-chloro-4-methoxy-pyrimidin-2-yl, 5-chloro-6-methoxy-pyrazin-2-yl,5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-methoxyphenyl,5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl,5-fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl,5-trifluoromethyl-pyrimidin-2-yl, 6-acetyl-pyridin-2-yl,6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-ethoxy-pyridin-2-yl,6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl,6-methoxy-5-methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl,6-methoxy-pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl,6-methylamino-pyrazin-2-yl, 6-methyl-pyridin-2-yl,5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and6-trifluoromethyl-pyridin-2-yl.

In other variations of the above embodiments and variations of theinvention, R₁₂, when present, is a five membered aryl or heteroaryl ofthe formula

wherein

J₀ is selected from the group consisting of N and C;

J₁ is selected from the group consisting of O, S, N, NR₁₃ and CR₁₄;

J₂ is selected from the group consisting of O, S, N, NR₁₅ and CR₁₆;

J₃ is selected from the group consisting of O, S, N, NR₁₇ and CR₁₈;

J₄ is selected from the group consisting of O, S, N, NR₁₉ and CR₂₀;

-   -   where        -   R₁₃, R₁₅, R₁₇, and R₁₉ are each individually selected from            the group consisting of hydrogen, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,            thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,            sulfinyl(C₁₋₁₀)alkyl, aza(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,            (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl,            hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and            hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;        -   R₁₄, R₁₆, R₁₈, and R₂₀ are each individually selected from            the group consisting of hydrogen, halo, nitro, cyano, thio,            oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,            hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl,            amino, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl,            (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,            thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,            sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)allyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted; and        -   one of R₁₃, R₁₄, R₁₉ and R₂₀ may be taken together with            R_(u) to form a 6 or 7 membered, saturated, unsaturated or            aromatic ring, each unsubstituted or further substituted            with 1-3 substitutents, and one of R₁₃, R₁₄, R₁₉ and R₂₀ may            be taken together with a substituent on the ring formed by            taking R₁₀ and R₁₁ together to form a 6 or 7 membered,            saturated, unsaturated or aromatic ring, each unsubstituted            or further substituted with 1-3 substituents.

In another variation, R₁₂, when present, is a six membered aryl orheteroaryl of the

wherein

J₀ is selected from the group consisting of N and C;

J₅ is selected from the group consisting of NR_(21′), CR₂₁ and C(O);

J₆ is selected from the group consisting of NR_(22′), CR₂₂ and C(O);

J₇ is selected from the group consisting of NR_(23′), CR₂₃ and C(O);

J₈ is selected from the group consisting of NR_(24′), CR₂₄ and C(O);

J₉ is selected from the group consisting of NR_(25′), CR₂₅ and C(O);

-   -   where        -   R₂₁, R_(21′), R₂₂, R_(22′), R₂₃, R_(23′), R₂₄, R_(24′), R₂₅            and R_(25′) are each individually selected from the group            consisting of hydrogen, halo, nitro, cyano, thio, alkylthio,            hydroxy, oxy, (C₁₋₁₀)alkoxy, (C₁₋₁₀)haloalkoxy, aryloxy,            heteroaryloxy, carbonyloxy, carbonyl, alkoxycarbonyl,            alkoxyaminocarbonyl, alkylaminocarbonyl, amino,            (C₁₋₁₀)alkylamino, hydroxy(C₁₋₁₀)alkylamino,            (C₁₋₁₀)alkylcarbonylamino, sulfonylamino,            alkylsulfonylamino, arylsulfonylamino, sulfonyl,            aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            hydroxy(C₁₋₁₀)alkyl, alkoxyalkyl, aryloxyalkyl,            carbonyl(C₁₋₁₀)alkyl, alkoxycarbonylalkyl,            aryloxycarbonylalkyl, thiocarbonyl(C₁₋₁₀)alkyl,            sulfonyl(C₁₋₁₀)alkyl, cycloalkylsulfonylalkyl,            sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,            alkoxycarbonylalkyl, aryloxyalkyl, heteroaryloxyalkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,            hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            unsubstituted or substituted with 1-4 substituents, and            R_(21′), R_(22′), R_(23′), R_(24′), and R_(25′) may be            individually absent when the nitrogen atom to which it is            bonded forms part of a double bond; and        -   one of R₂₁ and R₂₅ may be taken together with R₁₁ to form a            6 or 7 membered, saturated, unsaturated or aromatic ring,            each unsubstituted or further substituted with 1-3            substituents; and one of R₂₁ and R₂₅ may be taken together            with a substituent on the ring formed by taking R₁₀ and R₁₁            together to form a 6 or 7 membered, saturated, unsaturated            or aromatic ring, each unsubstituted or further substituted            with 1-3 substituents.

In one variation of the immediately above embodiments and variations,where R₁₂, when present, is a six membered aryl or heteroaryl of theformula

J₀ is selected from the group consisting of N and C; J₅ is N or CR₂₁where R₂₁ is hydrogen or fluoro; J₆ is N or CR₂₂ where R₂₂ is selectedfrom the group consisting of hydrogen, hydroxy, fluoro, methyl, ethyl,methoxy, and ethoxy; J₇ is N or CR₂₃ where R₂₃ is hydrogen or fluoro; J₈is N or CR₂₄ where R₂₄ is hydrogen or fluoro; and J₉ is N or CR₂₅ whereR₂₅ is hydrogen or fluoro. In another variation, J₀ is selected from thegroup consisting of N and C; J₅ is N; J₆ is N or C(OCH₃); J₇ is CH; J₈is CH; and J₉ is N or CH.

In yet another variation, R₁₂ is selected from the group consisting of:

In yet other variations, R₁₂ is selected from the group consisting of:

In still other variations, R₁₂ is of the formula

In another variation, when present, R₃ is selected from the groupconsisting of:

In still another variation, when present, R₃ is selected from the groupconsisting of:

In another variation, R₃, when present, is selected from the groupconsisting of:

In another variation, R₃, when present, is selected from the groupconsisting of:

In still another variation, R₃, when present, is selected from the groupconsisting of:

In another variation, R₃, when present, is selected from the groupconsisting of:

In still another variation, R₃, when present, is selected from the groupconsisting of:

In still another variation, R₃, when present, is selected from the groupconsisting of:

where

R₂₄ is selected from the group consisting of methoxy and ethoxy;

R₃₇ is selected from the group consisting of halo, alkoxy and alkyl,each unsubstituted or substituted; and

R₄₁ is selected from the group consisting of hydrogen, (C₁₋₆)oxaalkyland (C₁₋₆)alkyl.

In still another variation, R₃, when present, is selected from the groupconsisting of

In yet still another variation, R₃, when present, is

Particular examples of compounds according to the present inventioninclude, but are not limited to:

-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-methyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-methyl oxime-   (S,E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-methyl oxime-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-allyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-tert-butyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-isobutyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-benzyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-phenyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-4-nitrobenzyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-methoxyethyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-methoxyethyl oxime-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-methoxyethyl oxime-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-tert-butoxyethyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-3-methoxypropyl oxime;-   (E)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylideneaminooxy)acetic    acid;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(S)-2,3-dihydroxypropyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-aminoethyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-aminoethyl oxime;-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-2-aminoethyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-pyridin-3-ylmethyl oxime;-   (Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-pyridin-3-ylmethyl oxime;-   (E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-3-hydroxy-2-(hydroxymethyl)propyl oxime;-   (R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-3-hydroxy-2-(hydroxymethyl)propyl oxime;-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-3-hydroxy-2-(hydroxymethyl)propyl oxime;-   (E)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylidene)hydrazinecarboximidamide;-   (S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-2,3-dihydroxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3-hydroxy-2-(hydroxymethyl)propyl oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-3,4-dihydroxybutyl oxime;-   (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)amino)butane-1,2-diol;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((R)-1,4-dioxan-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-morpholin-2-ylmethyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-morpholin-2-ylmethyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-morpholin-2-ylmethyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3S,4R,5R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl    oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((3aR,4R,6R,    6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl    oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl    oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl    oxime;-   (R,Z)-2-amino-7-(3    ‘-(cyclopropylsulfonyl)-5-fluorobiphenyl-2-yl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-2,3-dihydroxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3S,4S)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    042S,4R)-4-hydroxypyrrolidin-2-yl)methyl oxime;-   (3R,5S)-1-acetyl-5-(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)pyrrolidin-3-yl    acetate,-   (2S,4R)-methyl    4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-2-carboxylate;-   (2S,4R)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-2-carboxylic    acid;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((2R,3R,4S)-3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3R,4S)-3,4-dihydroxycyclopentyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((3R,4S)-3,4-dihydroxycyclopentyl)methyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxy-4-methylpentyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    oxime;-   (R)-4-(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-2-morpholinoethyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(tetrahydro-2H-pyran-4-yl)methyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((1s,4S)-4-hydroxycyclohexyl)methyl oxime;-   (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-2-(morpholin-2-yl)ethyl oxime;-   (S)-44(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-3-benzyloxazolidin-2-one;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-2-amino-3-hydroxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(1-methyl-1H-imidazol-4-yl)methyl oxime;-   (R)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-5-imino-4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine;-   (R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(2-methoxythiazol-4-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyridol[4,3-d]pyrimidin-5(6H)-one    O—(S)-4,5-dihydroxypentyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3-amino-2-hydroxypropyl oxime;-   (S)-5(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3-hydroxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-4-hydroxybutyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3-hydroxy-2-methoxypropyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-4,5-dihydroxypentyl oxime;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(2-hydroxyethyl)-N-methylacetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylacetamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-14S)-3-hydroxypyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-fluoropyrrolidin-1-yl)ethanone;-   (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoic    acid;-   3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)    dihydrofuran-2(3H) one;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanamide;-   (S,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-3,4-dihydroxybutyl oxime;-   (S,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-3,4-dihydroxybutyl oxime;-   2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   (S)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   (R)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   (R)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   (S)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-1-morpholinobutan-1-one;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-methoxy-N,N-dimethylbutanamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-N—((S)-2,3-dihydroxypropyl)-N-methylacetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(2-hydroxyethyl)-N-methylacetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-bis(2-hydroxyethyl)acetamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-N,N-bis(2-hydroxypropyl)acetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(azetidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-hydroxypiperidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-((6-methylpyridin-2-yl)methyl)acetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-bis(2-methoxyethyl)acetamide;-   (R,Z)—N-(2-amino-2-oxo ethyl)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methylacetamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(2-methoxyethyl)-N-methylacetamide;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydroxypyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydr    oxy piperidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypiperidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3-hydroxyazetidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxy    pyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3,3-difluoropyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-fluoropyrrolidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-fluoropyrrolidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-methoxypiperidin-1-yl)ethanone-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3,3-difluoroazetidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(methoxymethyl)piperidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-(2-(methylamino)-2-oxoethyl)acetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(isoxazol-3-ylmethyl)-N-methylacetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-(thiazol-4-ylmethyl)acetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrazin-2-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(dimethylamino)piperidin-1-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(2-methyltetrahydro-1H-pyrrolo[3,4-c]pyridin-5    (6H,7H,7aH)-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)acetamide;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(2-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone;-   2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(hydroxymethyl)pyrrolidin-1-yl)ethanone;-   2-(2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)acetyl)hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3-methoxyazetidin-1-yl)ethanone;-   (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4,4-difluoropiperidin-1-yl)ethanone;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime;-   5(((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-3,4-dihydroxydihydrofuran-2(3H)-one;

5(((Z)—((R)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-3,4-dihydroxydihydrofuran-2(3H)-one;

-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7S,Z)-2-amino-8,8-difluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8,8-difluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxybutyl oxime;-   (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime;-   (7S,Z)-2-amino-8-fluoro-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7S,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-8-fluoro-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(3,4-dihydroxypyrrolidin-2-yl)methyl oxime;-   (7R,    Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3-amino-4-hydroxybutyl oxime;-   (7R,    Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-4-amino-3-hydroxybutyl oxime;-   (7R,    Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-2-amino-3-hydroxypropyl oxime; and-   (7R,    Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3-amino-2-hydroxypropyl oxime.

In another of its aspects, the present invention relates to process ofmaking compounds that are useful as HSP90 inhibitors.

In one embodiment, the process comprising:

reacting a compound having the formula

with a compound having the formula H₂N—O—R₁ under conditions that form aintermediate having the formula

reacting the intermediate with a compound having the formula

under conditions that form product having the formula

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)allyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)allyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₄₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted; and

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)allyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment of the process of making the compounds of theinvention comprises

reacting a compound having the formula

with a compound having the formula

under conditions that form an intermediate having the formula

and

reacting the intermediate with a compound having the formula H₂N—O—R₁under conditions that form a product having the formula

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,hydroxycarbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, (C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, carbonylamino(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, hydroxylcarbonyl(C₁₋₁₀)alkyl,aminocarbonyl(C₁₋₁₀)alkyl, aminosulfonyl(C₁₋₁₀)alkyl,sulfonylamino(C₁₋₁₀)alkyl, (C₁₋₆)alkylsulfonylamino(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted; and

R₂ is selected from the group consisting of hydrogen, halo, cyano, thio,hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In yet another embodiment of the process of making the compounds of theinvention comprising:

reacting a compound having the formula

with Starting Material I having the formula

under conditions that form Intermediate F having the formula

wherein

PG is a protecting group selected from the group consisting of((C₁₋₆)₃alkyl)silyl, (((C₁₋₆)alkyl)_(3-k))phenyl_(k))silyl where k is0-3, benzyl, and tetrahydropyranyl; and

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,halo(C₁₋₆)alkyl, aza(C₁₋₆)alkyl, (C₁₋₆)oxaalkyl, each unsubstituted orsubstituted.

In the above embodiment of the process, preparation of the compounds ofthe invention may be achieved via Method A comprising:

coupling Starting Material II having the formula

to said Intermediate F which form Intermediate G having the formula

coupling Starting Material III having the formula

to said Intermediate G under conditions that form Intermediate H havingthe formula

deprotecting said Intermediate H under conditions that form Producthaving the formula

wherein

R₁p is a protected form of R₁;

R₁ is selected from the group consisting of hydrogen, carbonyl,(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substitutedwith 1-3 substituents each of which is independently selected from thegroup consisting of hydroxyl, (C₁₋₁₀)allyl, hydroxy(C₁₋₁₀)alkyl, amino,amino(C₁₋₁₀)alkyl, aminocarbonyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each isunsubstituted or further substituted; and

R₁₂ is selected from a group consisting of (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,(C₃₋₁₂)cycloalkyl, and hetero(C₂₋₁₁)cycloalkyl, each unsubstituted orsubstituted with 1-3 substituents.

In the above embodiment of the process, preparation of the compounds ofthe invention may be achieved via Method B comprising:

deprotecting Intermediate F under conditions which form Intermediate F′having the formula

coupling Starting Material II having the formula

to said Intermediate F′which form Intermediate G having the formula

coupling Starting Material III having the formula

to said Intermediate G under conditions that form Intermediate H havingthe formula

deprotecting said Intermediate H under conditions that form Producthaving the formula

wherein

R₁ ^(p) is a protected form of

R₁ is selected from the group consisting of hydrogen, carbonyl,(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substitutedwith 1-3 substituents each of which is independently selected from thegroup consisting of hydroxyl, (C₁₋₁₀)allyl, hydroxy(C₁₋₁₀)alkyl, amino,amino(C₁₋₁₀)alkyl, aminocarbonyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each isunsubstituted or further substituted; and

R₁₂ is selected from a group consisting of (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,(C₃₋₁₂)cycloalkyl, and hetero(C₂₋₁₁)cycloalkyl, each unsubstituted orsubstituted with 1-3 substituents.

Another process which may be used to prepare the compounds of theinventions comprising:

reacting a compound having the formula

with Starting

Material I having the formula

under conditions that form Intermediate F having the formula

deprotecting said Intermediate F under conditions which formIntermediate F′ having the formula

coupling Starting Material III having the formula

to Intermediate F′ under conditions that form Intermediate J having theformula

deprotecting and then coupling Starting Material II having the formula

to Intermediate J under conditions which form Product having the formula

wherein

R₁ ^(p) is a protected form of R₁:

R₁ is selected from the group consisting of hydrogen, carbonyl,(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substitutedwith 1-3 substituents each of which is independently selected from thegroup consisting of hydroxyl, (C₁₋₁₀)allyl, hydroxy(C₁₋₁₀)alkyl, amino,amino(C₁₋₁₀)alkyl, aminocarbonyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each isunsubstituted or further substituted;

R₂ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,halo(C₁₋₆)alkyl, aza(C₁₋₆)alkyl, (C₁₋₆)oxaalkyl, each unsubstituted orsubstituted; and

R₁₂ is selected from a group consisting of (C₄₋₁₂)aryl,hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,(C₃₋₁₂)cycloalkyl, and hetero(C₂₋₁₁)cycloalkyl, each unsubstituted orsubstituted with 1-3 substituents.

In all the above embodiments of the processes, in some variations, R₁ is-L-R₄₅,

where

L is (—CR₄₆R₄₇—)—, where n is 1, 2, 3, 4, or 5; where R₄₆ and R₄₇ areeach independently selected from the group consisting of hydrogen,hydroxyl, hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy, oxo, amino, imino,(C₄₋₆)aryl(C₁₋₆)alkyl, hetero(C₁₋₅)aryl(C₁₋₆)alkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, hetero(C₁₋₅)cycloalkyl(C₁₋₆)alkyl,(C₄₋₆)aryl, hetero(C₁₋₅)aryl, (C₃₋₆)cycloalkyl, andhetero(C₁₋₅)cycloalkyl, each unsubstituted or substituted; and

R₄₅ is independently selected from the group consisting of hydrogen,hydroxyl, halo, (C₁₋₃)alkyl, hydroxy(C₁₋₃)alkyl, (C₁₋₃)alkoxy, amino,carbonylamino, aminocarbonyl, carbonyl, hydroxylcarbonyl, aryl,heteroaryl, cycloalkyl, and heterocycloalkyl, each unsubstituted orfurther substituted.

In other variations, R₁ is selected from the group consisting ofhydrogen,

In other variations, R₁ is selected from the group consisting of:hydrogen,

In still other variations, R₁ is selected from the group consisting of:

In still other variations, R₁ is selected from the group consisting ofhydrogen,

In still other variations, R₁ is selected from the group consisting ofhydrogen,

In some variation of the process of the invention, R₂ is selected fromthe group consisting of hydrogen, (C₁₋₆)alkyl, halo(C₁₋₆)alkyl,aza(C₁₋₆)allyl, (C₁₋₆)oxaallyl, each unsubstituted or substituted. Inother variations, R₂ is selected from the group consisting ofunsubstituted or substituted (C₁₋₆)alkyl. In still other variations, R₂is methyl. In yet still other variations, R₂ is hydrogen.

In the above embodiments of the processes of the invention, in somevariations, R₁₂ is selected from the group consisting of

In some other variations, R₁₂ is selected from the group consisting of

In still other variations, R₁₂ is of the formula

Another aspect of the invention relates to compounds that are useful forthe preparation of the compounds of the invention.

In one embodiment, intermediate compounds of the invention consisting ofthe formula:

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substitutedwith 1-3 substituents each of which is independently selected from thegroup consisting of hydroxyl, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, amino,amino(C₁₋₁₀)alkyl, aminocarbonyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each isunsubstituted or further substituted; and

X is a leaving group.

In yet another variation of the above embodiment of intermediatecompound, wherein the intermediate compound consisting of the formula:

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,sulfinyl(C₁₋₁₀)alkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each unsubstituted or substitutedwith 1-3 substituents each of which is independently selected from thegroup consisting of hydroxyl, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, amino,amino(C₁₋₁₀)alkyl, aminocarbonyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl, and hetero(C₁₋₁₀)aryl, each isunsubstituted or further substituted; and

X is a leaving group.

In some variations of the above embodiment and variations of theintermediate compounds of the invention, R₁ is selected from the groupconsisting of hydrogen,

In some other variations, R₁ is selected from the group consisting ofhydrogen,

In still other variations, R₁ is selected from the group consisting ofhydrogen,

In still other variations, R₁ is selected from the group consisting ofhydrogen,

In yet other variations, R₁ is selected from the group consisting of

In yet still other variations, R₁ is selected from the group consistingof hydrogen,

In yet still other variations, R₁ is selected from the group consistingof

In yet still other variations, R₁ is selected from the group consistingof

In yet still other variations, R₁ is

In yet still other variations, R₁ is

In yet still other variations, R₁ is

In yet still other variations, R₁ is

In some variations of the above embodiments and variations of thecompounds of the invention, R₁₂ is a leaving group selected from a groupconsisting of halo, and substituted and unsubstituted alkylsulfonate. Insome variations, R₁₂ is bromo. In other variations, R₁₂ is chloro.

In still other variations, R₁₂ is iodo. In still other variations, R₁₂is trifluoromethanesulfonate.

In another embodiment, the intermediate compound of the inventionconsisting of the formula:

wherein

R_(a) is selected from the group consisting of hydrogen, (C₁₋₆)alkyl,and a protecting group; and

R₁₂ is selected from a group consisting of (C₄₋₁₂)aryl andhetero(C₁₋₁₀)aryl, each unsubstituted or substituted, with 1-3substituents independently selected from the group consisting of halo,nitro, cyano, thio, alkylthio, (C₁₋₁₀)alkoxy, (C₁₋₁₀)haloalkoxy,hydroxy, aryloxy, heteroaryloxy, carbonyloxy, carbonyl,alkylaminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonylamino, sulfonyl,aminosulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)alkyl,alkoxyalkyl, alkoxycarbonylalkyl, aryloxyalkyl, heteroaryloxyalkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl.

In another variation of the immediate above embodiment, the intermediatecompounds of the invention are of the formula:

In some variations of the above embodiment and variations of thecompounds of the invention, R_(a) is hydrogen. In other variations,R_(a) is methyl. In other variations, R_(a) is a protecting groupselected from the group consisting of ((C₁₋₆)₃alkyl)silyl,(((C₁₋₆)allyl)_(3-n))phenyl_(n))silyl where n is 0-3, benzyl, andtetrahydropyranyl. In still other variations, R_(a) is selected from thegroup consisting trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl, and tert-butyldiphenylsilyl. In still othervariations, R_(a) is tert-butyldimethylsilyl. In still other variations,R_(a) is trimethylsilyl. In still other variation, R_(a) is benzyl. Inyet still other variations, R_(a) is tetrahydropyranyl.

In some variations of the above embodiment and variations of thecompounds of the invention, R₁₂ is phenyl or hetero(C₁₋₅)aryl, eachunsubstituted or substituted with said 1-3 substituents. In yet stillother variations, R₁₂ is selected from the group consisting of halo,

In still other variations, R₁₂ is selected from the group consisting ofbromo,

In still other variations, R₁₂ is

Particular examples of intermediate compounds according to the presentinvention include, but are not limited to:

-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-tert-butyldimethylsilyl oxime;-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(S)-3,4-dihydroxybutyl oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime;-   (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-(R)-2,3-dihydroxypropyl oxime;-   (R,Z)-2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetamide;-   (R,Z)-2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methylacetamide;    and-   (R,Z)-2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylacetamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas hydrogen.

It is further noted that the compound may be present as a mixture ofstereoisomers, or the compound may present as a single stereoisomer.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of the above embodiments and variations. In one particularvariation, the composition is a solid formulation adapted for oraladministration. In another particular variation, the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the composition is a tablet. In still anotherparticular variation, the composition is a liquid formulation adaptedfor parenteral administration.

The present invention also provides a pharmaceutical compositioncomprising a compound according to any one of the above embodiments andvariations, wherein the composition is adapted for administration by aroute selected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibitingHSP90 comprising contacting HSP90 with a compound of any one of theabove embodiments and variations.

In yet another of its aspects, there is provided a method of inhibitingHSP90 comprising causing a compound of any one of the above embodimentsand variations to be present in a subject in order to inhibit HSP90 invivo.

In a further of its aspects, there is provided a method of inhibitingHSP90 comprising administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits HSP90 in vivo, the second compound being a compound accordingto any one of the above embodiments and variations.

In another of its aspects, there is provided a method of treating adisease state for which HSP90 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising causing a compound of any one of the above embodiments andvariations to be present in a subject in a therapeutically effectiveamount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which HSP90 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a compound of any one of the above embodimentsand variations to a subject, wherein the compound is present in thesubject in a therapeutically effective amount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which HSP90 possesses activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits HSP90in vivo, the second compound being a compound according to any one ofthe above embodiments and variations.

In one variation of each of the above methods, the disease state isselected from the group consisting of cancer, inflammation, inflammatorybowel disease, psoriasis, arthritis, and transplant rejection.

In one variation of each of the above methods, the disease state iscancer. The cancer is selected from the group consisting of squamouscell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, nonsmall-cell lung cancer, bladder cancer, head and neck cancer, melanoma,ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer,glioma, colorectal cancer, genitourinary cancer, gastrointestinalcancer, renal cancer, hematological cancers, non-Hodgkin's lymphoma,lymphoma, multiple myeloma, leukemia (including acute myelogenousleukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia),myelodysplastic syndrome, and mesothelioma.

In one variation of each of the above methods, the HSP90 is an HSP90a.In another variation, the HSP90 is an HSP9013.

Salts, Hydrates, and Prodrugs of HSP90 Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfate, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptonate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine) It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basic nitrogencontaining groups may be quaternized with such agents as (C₁₋₄) alkylhalides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di(C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; andaryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide.Such salts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.,(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in P. G. M. Wuts and T. W. Greenein “Greene's Protective Groups in Organic Synthesis” 4th edition, JohnWiley and Sons, 2007.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Uses of the Compounds of the Invention

One set of indications that HSP90 inhibitors of the present inventionmay be used to treat are those involving undesirable or uncontrolledcell proliferation. Such indications include benign tumors, varioustypes of cancers such as primary tumors and tumor metastasis, restenosis(e.g. coronary, carotid, and cerebral lesions), abnormal stimulation ofendothelial cells (atherosclerosis), insults to body tissue due tosurgery, abnormal wound healing, diseases that produce fibrosis oftissue, repetitive motion disorders, disorders of tissues that are nothighly vascularized, proliferative responses associated with organtransplants, neurodegenerative disorders including Parkinson's,Alzheimer's, Huntington's and prion-related disease, inflammation andinflammation related disorders such as pain, headaches, fever,arthritis, asthma, bronchitis, tendonitis, eczema, inflammatory boweldisease, and the like, and diseases dependent on angiogenesis such as,cancer, arthritis, diabetic retinopathy, age associated maculardegeneration (AMD) and infectious diseases in particular fungalinfections, viral diseases including but not limited to diseases causedby hepatitis B virus (HBV), hepatitis C virus (HCV) and herpes simplexvirus type-1 (HSV-1), cardiovascular and central nervous systemdiseases^(3,4,5,6,7).

Generally, cells in benign tumors retain their differentiated featuresand do not divide in a completely uncontrolled manner. A benign tumor isusually localized and non-metastatic. Specific types of benign tumorsthat can be treated using HSP90 inhibitors of the present inventioninclude hemangiomas, hepatocellular adenoma, cavernous haemangioma,focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile ductadenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas,mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia,trachomas and pyogenic granulomas.

In the case of malignant tumors, cells become undifferentiated, do notrespond to the body's growth control signals, and multiply in anuncontrolled manner. Malignant tumors are invasive and capable ofspreading to distant sites (metastasizing). Malignant tumors aregenerally divided into two categories: primary and secondary. Primarytumors arise directly from the tissue in which they are found. Secondarytumors, or metastases, are tumors that originated elsewhere in the bodybut have now spread to distant organs. Common routes for metastasis aredirect growth into adjacent structures, spread through the vascular orlymphatic systems, and tracking along tissue planes and body spaces(peritoneal fluid, cerebrospinal fluid, etc.).

Specific types of cancers or malignant tumors, either primary orsecondary, that can be treated using the HSP90 inhibitors of the presentinvention include, but are not limited to, leukemia, breast cancer,genitourinary cancer, skin cancer, bone cancer, prostate cancer, livercancer, lung cancer, brain cancer, cancer of the larynx, gall bladder,pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder,head and neck, colon, stomach, colorectal, bronchi, kidneys, basal cellcarcinoma, squamous cell carcinoma of both ulcerating and papillarytype, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma,veticulum cell sarcoma, myeloma, giant cell tumor, small-cell lungtumor, non small-cell lung cancer, gallstones, islet cell tumor, primarybrain tumor, acute and chronic lymphocytic and granulocytic tumors,hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma,pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas,hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor,seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and insitu carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma,malignant carcinoid, topical skin lesion, gastrointestinal cancer,hematological cancers, myelodysplastic syndrome, mycosis fungoide,rhabdomyosarcoma, astrocytoma, non-Hodgkin's lymphoma, Kaposi's sarcoma,osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor,polycythermia vera, adenocarcinoma, glioblastoma multiforma, glioma,leukemia (including acute myelogenous leukemia, chronic myelogenousleukemia, chronic lymphocytic leukemia), lymphomas, malignant melanomas,epidermoid carcinomas, and other carcinomas and sarcomas.

The HSP90 inhibitors of the present invention may also be used to treatabnormal cell proliferation due to insults to body tissue duringsurgery. These insults may arise as a result of a variety of surgicalprocedures such as joint surgery, bowel surgery, and cheloid scarring.Diseases that produce fibrotic tissue include emphysema. Repetitivemotion disorders that may be treated using the present invention includecarpal tunnel syndrome. An example of a cell proliferative disorder thatmay be treated using the invention is a bone tumor.

Proliferative responses associated with organ transplantation that maybe treated using HSP90 inhibitors of the invention include proliferativeresponses contributing to potential organ rejections or associatedcomplications. Specifically, these proliferative responses may occurduring transplantation of the heart, lung, liver, kidney, and other bodyorgans or organ systems.

Abnormal angiogenesis that may be may be treated using this inventioninclude those abnormal angiogenesis accompanying rheumatoid arthritis,ischemic-reperfusion related brain edema and injury, cortical ischemia,ovarian hyperplasia and hypervascularity, (polycystic ovary syndrom),endometriosis, psoriasis, diabetic retinopaphy, and other ocularangiogenic diseases such as retinopathy of prematurity (retrolentalfibroplastic), macular degeneration, corneal graft rejection,neuroscular glaucoma and Oster Webber syndrome.

Examples of diseases associated with uncontrolled angiogenesis that maybe treated according to the present invention include, but are notlimited to retinal/choroidal neuvascularization and cornealneovascularization. Examples of retinal/choroidal neuvascularizationinclude, but are not limited to, Bests diseases, myopia, optic pits,Stargarts diseases, Pagets disease, vein occlusion, artery occlusion,sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum carotidabostructive diseases, chronic uveitis/vitritis, mycobacterialinfections, Lyme's disease, systemic lupus erythematosis, retinopathy ofprematurity, Eales disease, diabetic retinopathy, macular degeneration,Bechets diseases, infections causing a retinitis or chroiditis, presumedocular histoplasmosis, pars planitis, chronic retinal detachment,hyperviscosity syndromes, toxoplasmosis, trauma and post-lasercomplications, diseases associated with rubesis (neovascularization ofthe angle) and diseases caused by the abnormal proliferation offibrovascular or fibrous tissue including all forms of proliferativevitreoretinopathy. Examples of corneal neuvascularization include, butare not limited to, epidemic keratoconjunctivitis, vitamin A deficiency,contact lens overwear, atopic keratitis, superior limbic keratitis,pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,diabetic retinopathy, retinopathy of prematurity, corneal graftrejection, Mooren ulcer, Terrien's marginal degeneration, marginalkeratolysis, polyarteritis, Wegener sarcoidosis, scleritis, periphigoidradial keratotomy, neovascular glaucoma and retrolental fibroplasia,syphilis, Mycobacteria infections, lipid degeneration, chemical burns,bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpeszoster infections, protozoan infections and Kaposi sarcoma.

Chronic inflammatory diseases associated with uncontrolled angiogenesismay also be treated using HSP90 inhibitors of the present invention.Chronic inflammation depends on continuous formation of capillarysprouts to maintain an influx of inflammatory cells. The influx andpresence of the inflammatory cells produce granulomas and thus maintainsthe chronic inflammatory state Inhibition of angiogenesis using an HSP90inhibitor alone or in conjunction with other anti-inflammatory agentsmay prevent the formation of the granulosmas and thus alleviate thedisease. Examples of chronic inflammatory diseases include, but are notlimited to, inflammatory bowel diseases such as Crohn's disease andulcerative colitis, psoriasis, sarcoidois, and rheumatoid arthritis.

Inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis are characterized by chronic inflammation and angiogenesis atvarious sites in the gastrointestinal tract. For example, Crohn'sdisease occurs as a chronic transmural inflammatory disease that mostcommonly affects the distal ileum and colon but may also occur in anypart of the gastrointestinal tract from the mouth to the anus andperianal area. Patients with Crohn's disease generally have chronicdiarrhea associated with abdominal pain, fever, anorexia, weight lossand abdominal swelling. Ulcerative colitis is also a chronic,nonspecific, inflammatory and ulcerative disease arising in the colonicmucosa and is characterized by the presence of bloody diarrhea. Theseinflammatory bowel diseases are generally caused by chronicgranulomatous inflammation throughout the gastrointestinal tract,involving new capillary sprouts surrounded by a cylinder of inflammatorycells. Inhibition of angiogenesis by these inhibitors should inhibit theformation of the sprouts and prevent the formation of granulomas.Inflammatory bowel diseases also exhibit extra intestinalmanifestations, such as skin lesions. Such lesions are characterized byinflammation and angiogenesis and can occur at many sites other thegastrointestinal tract. Inhibition of angiogenesis by HSP90 inhibitorsaccording to the present invention can reduce the influx of inflammatorycells and prevent lesion formation.

Sarcoidosis, another chronic inflammatory disease, is characterized as amultisystem granulomatous disorder. The granulomas of this disease canform anywhere in the body. Thus, the symptoms depend on the site of thegranulomas and whether the disease is active. The granulomas are createdby the angiogenic capillary sprouts providing a constant supply ofinflammatory cells. By using HSP90 inhibitors according to the presentinvention to inhibit angiogenesis, such granulomas formation can beinhibited. Psoriasis, also a chronic and recurrent inflammatory disease,is characterized by papules and plaques of various sizes. Treatmentusing these inhibitors alone or in conjunction with otheranti-inflammatory agents should prevent the formation of new bloodvessels necessary to maintain the characteristic lesions and provide thepatient relief from the symptoms.

Rheumatoid arthritis (RA) is also a chronic inflammatory diseasecharacterized by non-specific inflammation of the peripheral joints. Itis believed that the blood vessels in the synovial lining of the jointsundergo angiogenesis. In addition to forming new vascular networks, theendothelial cells release factors and reactive oxygen species that leadto pannus growth and cartilage destruction. The factors involved inangiogenesis may actively contribute to, and help maintain, thechronically inflamed state of rheumatoid arthritis. Treatment usingHSP90 inhibitors according to the present invention alone or inconjunction with other anti-RA agents may prevent the formation of newblood vessels necessary to maintain the chronic inflammation and providethe RA patient relief from the symptoms.

Combination Therapy

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with HSP90 inhibitors according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: 1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; 2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or 3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. It is noted that combination therapy is intended tocover when agents are administered before or after each other(sequential therapy) as well as when the agents are administered at thesame time.

Examples of such therapeutic agents that may be used in combination withHSP90 inhibitors include, but are not limited to, anti-cellproliferation agents, anticancer agents, alkylating agents, antibioticagents, antimetabolic agents, hormonal agents, plant-derived agents, andbiologic agents.

Anti-cell proliferation agents are those which inhibit undesirable anduncontrolled cell proliferation. Examples of anti-cell proliferationagents that may be used in conjunction with the HSP90 inhibitors of thepresent invention include, but are not limited to, retinoid acid andderivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™ protein,ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor ofmetalloproteinase-I, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel, platelet factor 4, protaminesulphate (clupeine), sulphated chitin derivatives (prepared from queencrab shells), sulphated polysaccharide peptidoglycan complex (sp-pg),staurosporine, modulators of matrix metabolism, including for example,proline analogs (O-azetidine-2-carboxylic acid (LACA),cishydroxyproline, d,1-3,4-dehydroproline, thiaproline,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpha-2-antiplasmin, bisantrene, lobenzarit disodium,n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide, angostatic steroid, cargboxynaminolmidazole,metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents that may be used include antibodies, preferably monoclonalantibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5,VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. Ferrara N. and Alitalo,K. “Clinical application of angiogenic growth factors and theirinhibitors” (1999) Nature Medicine 5:1359-1364.

Alkylating agents are polyfunctional compounds that have the ability tosubstitute alkyl groups for hydrogen ions. Examples of alkylating agentsinclude, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). These compounds react with phosphate, amino, hydroxyl,sulfihydryl, carboxyl, and imidazole groups. Under physiologicalconditions, these drugs ionize and produce positively charged ion thatattach to susceptible nucleic acids and proteins, leading to cell cyclearrest and/or cell death. Combination therapy including an HSP90inhibitor and an alkylating agent may have therapeutic synergisticeffects on cancer and reduce sides affects associated with thesechemotherapeutic agents.

Antibiotic agents are a group of drugs that produced in a manner similarto antibiotics as a modification of natural products. Examples ofantibiotic agents include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interfere with cell growth by targeting different cellularcomponents. For example, anthracyclines are generally believed tointerfere with the action of DNA topoisomerase II in the regions oftranscriptionally active DNA, which leads to DNA strand scissions.Bleomycin is generally believed to chelate iron and forms an activatedcomplex, which then binds to bases of DNA, causing strand scissions andcell death. Combination therapy including an HSP90 Inhibitor and anantibiotic agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Antimetabolic agents are a group of drugs that interfere with metabolicprocesses vital to the physiology and proliferation of cancer cells.Actively proliferating cancer cells require continuous synthesis oflarge quantities of nucleic acids, proteins, lipids, and other vitalcellular constituents. Many of the antimetabolites inhibit the synthesisof purine or pyrimidine nucleosides or inhibit the enzymes of DNAreplication. Some antimetabolites also interfere with the synthesis ofribonucleosides and RNA and/or amino acid metabolism and proteinsynthesis as well. By interfering with the synthesis of vital cellularconstituents, antimetabolites can delay or arrest the growth of cancercells. Examples of antimetabolic agents include, but are not limited to,fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin,hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine,pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase,and gemcitabine. Combination therapy including an HSP90 inhibitor and anantimetabolic agent may have therapeutic synergistic effects on cancerand reduce sides affects associated with these chemotherapeutic agents.

Hormonal agents are a group of drug that regulate the growth anddevelopment of their target organs. Most of the hormonal agents are sexsteroids and their derivatives and analogs thereof, such as estrogens,androgens, and progestins. These hormonal agents may serve asantagonists of receptors for the sex steroids to down regulate receptorexpression and transcription of vital genes. Examples of such hormonalagents are synthetic estrogens (e.g. diethylstibestrol), antiestrogens(e.g. tamoxifen, toremifene, fluoxymesterol and raloxifene),antiandrogens (bicalutamide, nilutamide, and flutamide), aromataseinhibitors (e.g., aminoglutethimide, anastrozole and tetrazole),ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone. Combination therapy including an HSP90 inhibitor and ahormonal agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Plant-derived agents are a group of drugs that are derived from plantsor modified based on the molecular structure of the agents. Examples ofplant-derived agents include, but are not limited to, vinca alkaloids(e.g., vincristine, vinblastine, vindesine, vinzolidine andvinorelbine), podophyllotoxins (e.g., etoposide (VP-16) and teniposide(VM-26)), and taxanes (e.g., paclitaxel and docetaxel). Theseplant-derived agents generally act as antimitotic agents that bind totubulin and inhibit mitosis. Podophyllotoxins such as etoposide arebelieved to interfere with DNA synthesis by interacting withtopoisomerase II, leading to DNA strand scission. Combination therapyincluding an HSP90 inhibitor and a plant-derived agent may havetherapeutic synergistic effects on cancer and reduce sides affectsassociated with these chemotherapeutic agents.

Biologic agents are a group of biomolecules that elicit cancer/tumorregression when used alone or in combination with chemotherapy and/orradiotherapy. Examples of biologic agents include, but are not limitedto, immuno-modulating proteins such as cytokines, monoclonal antibodiesagainst tumor antigens, tumor suppressor genes, and cancer vaccines.Combination therapy including an HSP90 inhibitor and a biologic agentmay have therapeutic synergistic effects on cancer, enhance thepatient's immune responses to tumorigenic signals, and reduce potentialsides affects associated with this chemotherapeutic agent.

Cytokines possess profound immunomodulatory activity. Some cytokinessuch as interleukin-2 (IL-2, aldesleukin) and interferon havedemonstrated antitumor activity and have been approved for the treatmentof patients with metastatic renal cell carcinoma and metastaticmalignant melanoma. IL-2 is a T-cell growth factor that is central toT-cell-mediated immune responses. The selective antitumor effects ofIL-2 on some patients are believed to be the result of a cell-mediatedimmune response that discriminate between self and nonself. Examples ofinterleukins that may be used in conjunction with HSP90 inhibitorsinclude, but are not limited to, interleukin 2 (IL-2), and interleukin 4(IL-4), interleukin 12 (IL-12).

Interferon include more than 23 related subtypes with overlappingactivities, all of the IFN subtypes within the scope of the presentinvention. IFN has demonstrated activity against many solid andhematologic malignancies, the later appearing to be particularlysensitive.

Other cytokines that may be used in conjunction with an HSP90 inhibitorinclude those cytokines that exert profound effects on hematopoiesis andimmune functions. Examples of such cytokines include, but are notlimited to erythropoietin, granulocyte-CSF (filgrastin), andgranulocyte, macrophage-CSF (sargramostim). These cytokines may be usedin conjunction with an HSP90 inhibitor to reduce chemotherapy-inducedmyelopoietic toxicity.

Other immuno-modulating agents other than cytokines may also be used inconjunction with an HSP90 inhibitor to inhibit abnormal cell growth.Examples of such immuno-modulating agents include, but are not limitedto bacillus Calmette-Guerin, levamisole, and octreotide, a long-actingoctapeptide that mimics the effects of the naturally occurring hormonesomatostatin.

Monoclonal antibodies against tumor antigens are antibodies elicitedagainst antigens expressed by tumors, preferably tumor-specificantigens. For example, monoclonal antibody HERCEPTIN® (Trastruzumab) israised against human epidermal growth factor receptor2 (HER2) that isoverexpressed in some breast tumors including metastatic breast cancer.Overexpression of HER2 protein is associated with more aggressivedisease and poorer prognosis in the clinic. HERCEPTIN® is used as asingle agent for the treatment of patients with metastatic breast cancerwhose tumors over express the HER2 protein. Combination therapyincluding HSP90 inhibitor and HERCEPTIN® may have therapeuticsynergistic effects on tumors, especially on metastatic cancers.

Another example of monoclonal antibodies against tumor antigens isRITUXAN® (Rituximab) that is raised against CD20 on lymphoma cells andselectively deplete normal and malignant CD20⁺pre-B and mature B cells.RITUXAN® is used as single agent for the treatment of patients withrelapsed or refractory low-grade or follicular, CD20⁺, B cellnon-Hodgkin's lymphoma. Combination therapy including an HSP90 inhibitorand RITUXAN® may have therapeutic synergistic effects not only onlymphoma, but also on other forms or types of malignant tumors.

Tumor suppressor genes are genes that function to inhibit the cellgrowth and division cycles, thus preventing the development ofneoplasia. Mutations in tumor suppressor genes cause the cell to ignoreone or more of the components of the network of inhibitory signals,overcoming the cell cycle check points and resulting in a higher rate ofcontrolled cell growth-cancer. Examples of the tumor suppressor genesinclude, but are not limited to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1and BRCA2. DPC-4 is involved in pancreatic cancer and participates in acytoplasmic pathway that inhibits cell division. NF-1 codes for aprotein that inhibits Ras, a cytoplasmic inhibitory protein. NF-1 isinvolved in neurofibroma and pheochromocytomas of the nervous system andmyeloid leukemia. NF-2 encodes a nuclear protein that is involved inmeningioma, schwanoma, and ependymoma of the nervous system. RB codesfor the pRB protein, a nuclear protein that is a major inhibitor of cellcycle. RB is involved in retinoblastoma as well as bone, bladder, smallcell lung and breast cancer. P53 codes for p53 protein that regulatescell division and can induce apoptosis. Mutation and/or inaction of p53are found in wide ranges of cancers. WTI is involved in Wilms tumor ofthe kidneys. BRCA1 is involved in breast and ovarian cancer, and BRCA2is involved in breast cancer. The tumor suppressor gene can betransferred into the tumor cells where it exerts its tumor suppressingfunctions. Combination therapy including an HSP90 inhibitor and a tumorsuppressor may have therapeutic synergistic effects on patientssuffering from various forms of cancers.

Cancer vaccines are a group of agents that induce the body's specificimmune response to tumors. Most of cancer vaccines under research anddevelopment and clinical trials are tumor-associated antigens (TAAs).TAA are structures (i.e. proteins, enzymes or carbohydrates) which arepresent on tumor cells and relatively absent or diminished on normalcells. By virtue of being fairly unique to the tumor cell, TAAs providetargets for the immune system to recognize and cause their destruction.Example of TAAs include, but are not limited to gangliosides (GM2),prostate specific antigen (PSA), α-fetoprotein (AFP), carcinoembryonicantigen (CEA) (produced by colon cancers and other adenocarcinomas, e.g.breast, lung, gastric, and pancreas cancers), melanoma associatedantigens (MART-1, gp100, MAGE 1,3 tyrosinase), papillomavirus E6 and E7fragments, whole cells or portions/lysates of antologous tumor cells andallogeneic tumor cells.

An adjuvant may be used to augment the immune response to TAAs. Examplesof adjuvants include, but are not limited to, bacillus Calmette-Guerin(BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH),interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor(GM-CSF) and cytoxan, a chemotherapeutic agent which is believe toreduce tumor-induced suppression when given in low doses.

Compositions Comprising HSP90 Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The HSP90 inhibitors and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a HSP90 inhibitor, in the course of a coordinated treatment toachieve an improved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerin, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfate; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyvinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practices of Pharmacy, Lippincott Williams, and WilkinsPublisher, 21^(st) edition, 2005. The composition or formulation to beadministered will, in any event, contain a sufficient quantity of aninhibitor of the present invention to reduce HSP90 activity in vivo,thereby treating the disease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more HSP90 inhibitors, optionally 0.1-95%, andoptionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

A. Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose, and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol, and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurate,and polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

B. Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions includes EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is known and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the HSP90 inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The HSP90 inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined

C. Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a HSP90 inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

D. Formulation for Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The HSP90 inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the HSP90 inhibitor alone or in combination withother pharmaceutically acceptable excipients can also be administered.

E. Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

F. Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention  1%Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica  1%.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas HSP90 inhibitors for a variety of subjects (e.g., humans, non-humanmammals and non-mammals).

The optimal dose may vary depending upon such conditions as, forexample, the type of subject, the body weight of the subject, on theseverity of the condition, the route of administration, and specificproperties of the particular compound being used. Generally, acceptableand effective daily doses are amounts sufficient to effectively slow oreliminate the condition being treated. Typically, the daily dose fororal administration to an adult (body weight of about 60 kg) is about 1to 1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Kits and Articles of Manufacture Comprising HSP90 Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with HSP90. It is noted that diseasesare intended to cover all conditions for which the HSP90 possessactivity that contributes to the pathology and/or symptomology of thecondition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Preparation of HSP90 Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee P. G. M. Wuts and T. W. Greene in “Greene's Protective Groups inOrganic Synthesis” 4th edition, John Wiley and Sons, 2007.

Reaction of aldehyde 1A with acetone derivative 1B gives enone 1C (Step1). Treatment of enone 1C with malonate derivative 1D followed bysaponification and decarboxylation gives vinylogous acid 1E (Step 2).C-acylation with acid chloride 1F gives trione 1G (Step 3). Treatment of1G with guanidine in the presence of pyrrolidine givesdihydroquinazolinone 1H (Step 4). Suzuki coupling with boronic ester 11(Step 5) gives compound 1J. Reaction with alkoxyamine 1K in refluxingpyridine (Step 6), and, if necessary, deprotection (Step 7), gives oximeether 1L. Chiral separation via SFC gives both enantiomers, 1M and 1N.

The reaction of aldehyde 2A with chiral sulfinamide 2B in the presenceof titanium tetraethoxide gives imine 2C (Step 1). Treatment of thesulfinamide with the Reformatsky reagent of 2D exclusively gives chiralsulfinamide 2E (Step 2) which is followed by acid-catalyzed deprotectionto give chiral beta-amino acid 2F (Step 3). Reaction of the amine withfunctionalized diketene 2G gives amide 2H (Step 4) which is followed bytreatment with methoxide to form Dieckmann condensation product 21 (Step5). Reaction of the vinylogous acid 21 with acetylguanidine givescondensation product 2J (Step 6). Conversion of lactam 2J to thethiolactam 2K is effected with a thiolating reagent such as Davy's orLawesson's reagent (Step 7). Conversion of thiolactam 2K to the amidine2M is achieved by treatment with substituted alkoxyamine 2L (Step 8).Lastly, Suzuki coupling with boronic ester 2N (Step 9) and, ifnecessary, deprotection (Step 10), gives final product 20.

Reaction of aldehyde 3A with acetone derivative 3B gives enone 3C (Step1). Treatment of enone 3C with malonate derivative 3D followed bysaponification and decarboxylation gives vinylogous acid 3E (Step 2).C-acylation with acid chloride 3F gives trione 3G (Step 3). Acetylationof the vinylogous acid gives 3H (Step 4), which is in turn subjected tomalononitrile under basic conditions to give 31 (Step 5). Treatment ofbisnitrile 31 with ammonia gives aminopyridine 3J (Step 6). Suzukicoupling with boronic ester 3K (Step 7) gives compound 3L. Reaction withalkoxyamine 3M in refluxing pyridine (Step 8), and, if necessary,deprotection (Step 9), gives oxime ether 3N. Chiral separation via SFCgives both enantiomers, 30 and 3P.

Furthermore, 3L may be manipulated with the following series oftransformations to access various R₇ moieties. Aminopyridine 3L isprotected as its acetyl derivative 3Q (Step 10). Treatment of nitrile 3Qwith HCl gives acid 3R (Step 11). Curtius rearrangement induced bydiphenylphosphoryl azide (Step 12) gives aniline 3S. Finally aniline 3Scan be converted to phenol 3T via Sandmeyer chemistry. Any of theintermediates 3Q, 3R, 3S, and 3T may be functionalized as in Steps 8 and9 to give the corresponding oxime ethers, followed by chiral separationvia SFC.

The reaction of aldehyde 4A with chiral sulfonamide 4B in the presenceof titanium tetraethoxide gives imine 4C (Step 1). Treatment of thesulfinamide with the Reformatsky reagent 4D exclusively givesenantiopure sulfonamide 4E (Step 2) which is followed by acid-catalyzeddeprotection to give beta-amino acid 4F (Step 3). Reaction of the aminewith functionalized diketene 4G gives amide 4H (Step 4) which isfollowed by treatment with methoxide to give Dieckmann condensationproduct 4I (Step 5). After oxidation, reaction of the bisnitrile 4I withammonia gives condensation product 4J (Step 6). Conversion of lactam 4Jto the thiolactam 4K is effected with a thiolating reagent such asDavy's or Lawesson's reagent (Step 7). Conversion of thiolactam 4K tothe amidine 4M is achieved by treatment with substituted alkoxyamine 4L(Step 8). Lastly, Suzuki coupling with boronic ester 4N (Step 9) and, ifnecessary, deprotection (Step 10), gives final product 4O.

The reaction of thiolactam 2K with protected hydroxylamine 5A (e.g., TBSprotected) in the presence of mercuric acetate yields amidine 5B, whichis followed by acid catalyzed deprotection to give hydroxyl derivative5C. Alkylation with the appropriate haloalkyl 5D in base, e.g., Cs₂CO₃,yields oxime ether 5E, followed by a coupling reaction such as Suzukicoupling with boronic acid 5C, and if necessary deprotection givesproduct 5F.

The reaction of thiolactam 2K with protected hydroxylamine 6A (e.g., TBSprotected) in the presence of a strong thiophile (e.g., mercuricacetate) yields amidine 6B. Arylation reaction (e.g Suzuki coupling)with boronic ester 6C and deprotection to give hydroxyl derivative 6D.Alkylation with the appropriate haloalkyl 6E in base, e.g., Cs₂CO₃,gives product 6F.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

General Procedures

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in P. G. M. Wuts and T. W. Greene, “Greene'sProtecting Groups in Organic Synthesis”, 4^(th) edition, John Wiley &Sons, Inc. 2007.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

The present invention also provides(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(611)-oneO-(S)-3,4-dihydroxybutyl oxime benzoate Form A. The formation of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime benzoate Form A is generally carried outby crystallization from a solvent. In practice suitable solvents includechloroform, toluene, acetonitrile, and acetone. Anti-solvents, that is,a solvent or solvents in which the compound is less soluble than in theselected solvent can also be used. The volume of solvent is not criticalbut should be kept to a minimal amount as a matter of convenience.Optionally, the crystallization may be seeded with Form A. Suchprocesses generally require 2 hours to seven days. It is understood thatthe terms “crystallize,” “crystallizing,” and “crystallization” tocomplete dissolution followed by precipitation and slurry processes thatdo not involve complete dissolution.

(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime benzoate Form A can be characterized byX-ray diffraction. A powder X-ray diffractogram of Form A obtained bystandard powder X-ray diffraction technique is provided in FIG. 2.Standard powder diffractometers are generally equipped with a coppersource, primary beam monochromator, and position sensitive detector. Theincident beam is typically collimated using a divergence slit to around1°. The source generally operated at 40 kV and 30 mA. X-ray powderdiffraction data may be collected from 3 degrees to 120 degrees twotheta using a step width of 0.02 to 0.04 degrees two theta. Thediffractometer can be calibrated with a silicon standard or othersuitable standard materials. Many modern diffractometers are alsoequipped with a goniometer head that can be motorized to permit spinningof the sample during data acquisition. It is recognized that therelative intensity of X-ray diffraction peaks can be dependent onpreferred orientation and other factors. Therefore, a sample of Form Amay require processing to mitigate such factors, such as grinding thesample in an agate mortar and pestle or other measures. It is understoodthat differences in relative intensity of the diffraction peaks does notpreclude an acquired pattern from being consistent with(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl benzoate Form A. Further it is also understoodthat only a subset of the peaks shown in FIG. 2, in some instances asfew as one peak, are required to identify(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl benzoate Form A.

Form A can also be characterized by thermal analysis, typicallydifferential scanning calorimetry (DSC) and thermogravimetry. FIG. 3shows DSC and therogravimetry thermograms of Form A. The DSC thermogramshows a single endothermic event at 128° C. which was consistent with amelt.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphosphatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine SerumAlbumin) CBZ (benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid chromatography) Hz(Hertz) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)r.t. (ambient temperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time) Brij35(polyoxyethyleneglycol dodecyl ether)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at r.t. unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E Merck silica gel plates (60E-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-23, John Wiley and Sons, New York, N.Y., 2006; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1998; Organic Reactions, vols. 1-68, John Wiley and Sons,New York, N.Y., 2007; March J.: Advanced Organic Chemistry, 5th ed.,2001, John Wiley and Sons, New York, N.Y.; and Larock: ComprehensiveOrganic Transformations, 2^(nd) edition, John Wiley and Sons, New York,1999. The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques, AndreCollet, and Samuel H. Wilen, Enantiomers, Racemates and Resolutions,John Wiley & Sons, Inc. (1981).

Diastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and can be readilyseparated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques, Andre Collet, and Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Waters ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 100. In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction schemes and variationsthereof are set forth in the Example section.

Assaying the Biological Activity of the Compounds of the Invention

The inhibitory effect of the compound of the invention on HSP90 may beevaluated by a variety of binding assays and functional assays. It iswell known that binding to the N-terminal ATP-binding domain of HSP90inhibits ATP binding and ATP-dependent chaperone activities, Roe et al.J. Med. Chem. 1999 42, 260-266. A variety of in vitro and in vivobinding assays are available in the literature for assessing theaffinity of the compounds of the invention on HSP90; e.g., Chiosis etal. Chemistry & Biology 2001 8: 289-299, Carreras et al. Anal Biochem2003 317(1): 40-6; Kim et al. J Biomol Screen 2004 9(5): 375-81; andZhou et al. Anal Biochem 2004 331(2): 349-57.

Example A-1 below provides an in vitro competition fluorescencepolarization assay in which a test compound competes with a fluorescentprobe for binding to the binding domain of human recombinant HSP90. Thereaction can be followed kinetically using fluorescence (excitationλ=485 nm; emission λ=538 nm). The binding affinity of the test compoundto HSP90 is determined by the changes in the polarized fluorescence; theintensity of the polarized fluorescence is proportional to the fractionof bound probe. A novel small molecule fluorescence probe,(S,E)-5-(2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylideneaminooxy)ethylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid (TSD-FP probe) was specifically developed for the assay. Inhibitionconstants (IC₅₀) may be calculated by non-linear curve fitting of thecompound concentrations and fluorescence intensities to the standardIC₅₀ equation. As reference, the IC₅₀ values by this assay for the twoknown HSP90 inhibitors geldanamycin (GM) and17-allylamino,17-demethoxygeldanamycin (17-AAG) after one hourincubation with the enzyme and the TSD-FP probe were 90 nM and 400 nM,respectively. Using the procedure described in Example A-1, some of theexemplified compounds were shown to have HSP90 binding affinity at anIC₅₀ of less than 10 μM, some others less than about 1 μM, and mostothers of the compounds have an IC₅₀ value of less than about 0.1 μM.The IC₅₀ values of the exemplified compounds of the present inventionare given in Table 1.

The inhibitory effect of the compounds of the invention against HSP90 inlive cells may be evaluated by measuring cell viability. Example A-2described a cell viability assay where exponentially growing tumor cellswere exposed to a range of drug concentrations. After the drugtreatment, the viability of the cells was measured by the conversion oftetrazolium salts MTS (3-[4,5,dimethylthiazol-2-yl]-5-[3-carboxymethoxy-phenyl]-2-[4-sulfophenyl]-2H-tetrazolium,inner salt), (Promega, Madison, Wis.) by metabolically active cells.Further, the selected cancer cell panel includes BT-474, HT-29, K-562,and MKN-45 cells each of which represents a different cancer type and awell understood route of oncogenic transformation.

Downstream effects of HSP90 inhibition can be evaluated based on theinduction of HSP70 and on the function and stability of various steroidreceptors and signaling proteins including, e.g., HER2/ERBB2. HSP70induction is a hallmark of HSP90 inhibition. HSP70 as an ATP dependentheat shock protein itself will be transcriptionally up-regulated inresponse to misfolded, denatured or aggregated proteins. As HSP90function becomes compromised, HSP70 is induced in direct response toHSP90 client protein changes within the cell. Guo et al. Cancer Res 200565(22) 10536. Example A-3 provides a method to quantify HSP70 inductionby monitoring the non-infrared luminescence of β-galactosidase, anddetermine the EC₅₀ values of the test compounds forHSP70β/β-galactosidase induction.

The depletion of HER-2/ERBB2 oncoprotein is also a hallmark of HSP90inhibition. Sain et al. Mol Cancer Ther 2006 5(5) 1197; Sharp et al. MolCancer Ther 2007 6(4) 1198. HER-2 uses HSP90 for maturation;perturbations in HSP90 function lead to misfolded proteins thatultimately will be sent for ubiquitination and proteasomal degradation.Compounds of the present invention induce degradation of thesemolecules, which can be measured using well known antibody techniquessuch as immunoblotting, radioimmunoassays, Western blotting,immunoprecipitation, enzyme-linked immunosorbant assays (ELISA), andderivative techniques that make use of antibodies directed against HER2.Example A-4 provides a Western blotting procedure for the determinationof the EC₅₀ value of the test compounds for depletion of HER2/ERBB2.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

EXAMPLE Example 1 General Procedure for the Preparation of Oxime Ethersand Analogs

A. (E)-4-(2-Bromo-4-fluorophenyl)but-3-en-2-one (1B)

To a 500 mL recovery flask was added 2-bromo-4-fluorobenzaldehyde (1A,10.0 g, 49.3 mmol, 1.0 eq.) and acetone (22.9 g, 394 mmol, 8.0 eq.). Themixture was cooled to 0° C. in an ice bath. H₂O (200 mL) was added andthe mixture became a thick suspension. Solid NaOH (2.16 g, 54.2 mmol,1.1 eq.) was added and the reaction was gradually warmed to roomtemperature and stirred overnight. The reaction was acidified with 1NHCl and extracted with EtOAc (3×100 mL). The organic phases werecombined and washed with saturated aqueous NaCl. The organic phase wasdried over anhydrous Na₂SO₄, filtered, and concentrated to give a darkyellow oil that was carried on to the next step without furtherpurification (11.9 g, 99%). ESI-MS: m/z 243.2 (M+H)⁺.

B. 5-(2-Bromo-4-fluorophenyl)-3-hydroxycyclohex-2-enone (1D)

To a 500 mL recovery flask was added(E)-4-(2-bromo-4-fluorophenyl)but-3-en-2-one (1B, 11.9 g, 49.0 mmol, 1.0eq.) and MeOH (200 mL). Dimethyl malonate (1C, 6.47 g, 49.0 mmol, 1.0eq.) was added, followed by NaOMe (30% wt in MeOH, 9.6 mL, 51.4 mmol,1.05 eq.). The reaction mixture was refluxed overnight upon which it wasconcentrated to a brownish-red solid. The residue was taken up in 1NNaOH (150 mL) and refluxed for 1 h, during which the reaction colorproceeded from cloudy-brown, to clear brown, to clear solution withbrown precipitate. Concentrated HCl was carefully added until themixture was acidic by pH paper. The reaction mixture was diluted withEtOAc (200 mL) and washed with saturated aqueous NaCl. The aqueous phasewas extracted with EtOAc (lx 75 mL). The organic phase was dried overanhydrous Na₂SO₄, filtered, and concentrated to give a foamy orangesolid that was carried on to the next step without further purification(14.3 g, 100%). ESI-MS: m/z 285.2 (M+H)⁺.

C.5-(2-Bromo-4-fluorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione(1E)

To a 500 mL recovery flask was added5-(2-bromo-4-fluorophenyl)-3-hydroxycyclohex-2-enone (1D) (14.3 g, 50.1mmol, 1.0 eq.), CH₂Cl₂ (200 mL), acetic anhydride (6.65 g, 65.2 mmol,1.3 eq.), Et₃N (15.22 g, 150 mmol, 3.0 eq.), and DMAP (catalyticamount). The reaction mixture was stirred overnight at room temperature.Monitoring by LC/MS judged the reaction to be complete. The reactionmixture was concentrated and purified via column chromatography(gradient 70% CH₂Cl₂/Hex to 100% CH₂Cl₂) to yield the product as lightyellow foam which later became an oil (3.55 g, 22%). The crude materialwas used in the next step without further purification. ESI-MS: m/z327.2 (M+H)⁺.

D.2-Amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1F)

To a 150 mL pressure vessel was added5-(2-bromo-4-fluorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione(1E, 1.12 g, 3.42 mmol, 1.0 eq.), EtOH (30 mL), guanidine hydrochloride(818 mg, 8.56 mmol, 2.5 eq.), and dimethylamine (2.0 M in THF, 10 mL,20.5 mmol, 6.0 eq.). The vessel was sealed and heated for 72 hours at100° C. LC/MS determined the reaction to be complete. The reaction wascooled and concentrated to give a pasty gray solid. EtOH (−10 mL) wasadded to the residue and sonicated to give a suspension. The solid wascollected by filtration and rinsed with cold EtOH to give a light-yellowsolid (288 mg, 24%). ESI-MS: m/z 350.2 (M+H)⁺.

E.2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H)

To a 10 mL recovery flask was added2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(33 mg, 0.0942 mmol, 1.0 eq.), 2-fluoropyridine-3-boronic acid (27 mg,0.188 mmol, 2.0 eq.), DME (2 mL), potassium carbonate (2.0M aq., 94 μL,0.188 mmol, 2.0 eq.), and palladium tetrakis triphenylphosphine (5 mg,0.00471 mmol, 0.05 eq.). The reaction was refluxed overnight whereuponLC/MS analysis judged the reaction to be complete. The reaction mixturewas filtered through Celite and concentrated to a residue. The residuewas purified via preparatory-HPLC to give the product white solid (30mg, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.67 (dd, J=3.54, 1.77 Hz, 1H)2.89 (br. s., 1H) 3.06 (t, J=12.51 Hz, 2 H) 3.18 (br. s., 1H) 7.18 (dd,J=9.60, 2.78 Hz, 1H) 7.31-7.53 (m, 4H) 7.72 (dd, J=8.84, 5.81 Hz, 1H)7.98 (ddd, J=9.79, 7.52, 1.89 Hz, 1H) 8.28 (d, J=4.80 Hz, 1H). ESI-MS:m/z 367.3 (M+H)⁺. ESI-MS: m/z 367.3 (M+H)⁺.

F. Formation of Oxime Ethers

Oxime ethers may be formed by either Method A or Method B below.

Method A, basic conditions: A solution of2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H, 0.27 mmol, 1.0 eq.) and the corresponding hydroxylamine 1I (0.54mmol, 2.0 eq.) in dry pyridine (2 mL) were stirred overnight at 75° C.The mixture was poured into ice water and the resulting precipitate wascollected by filtration. The crude solid was recrystallized in hotethanol to yield pure product 1J as a white solid in 90% yield.

Method B, acidic conditions: A solution of2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H, 0.27 mmol, 1.0 eq.) in EtOH (3 mL) was stirred under nitrogen. Thecorresponding hydroxylamine 1I (0.35 mmol, 1.3 eq.) and aqueous HCl (5M,0.48 mmol, 1.8 eq.) were added and the reaction was heated to reflux for4 h. The reaction mixture was cooled to room temperature andconcentrated. The resulting residue was collected and recrystallized inhot ethanol to obtain pure product 1J as a white or off-white powder inabout 90% yield.

Example 2 Preparation of Hydroxylamine Reagents A. Synthesis ofO-(2-methoxyethyl)hydroxylamine (2B)

Step 1: 2-methoxyethanol (2.00 g, 26.3 mmol), N-hydroxyphthalimide (4.72g, 28.9 mmol, 1.1 eq., and triphenylphosphine (7.58 g, 28.9 mmol, 1.1eq.) were dissolved in 85 mL of dry THF and then the mixture was cooledin an ice bath. Diisopropyl azodicarboxylate (6.91 g, 34.2 mmol, 1.3eq.) was dissolved in 15 mL of dry THF and was added slowly to the abovemixture. The reaction was stirred in the ice bath for 10 minutes andthen the ice bath was removed. The reaction then was allowed to stir atroom temperature under N₂ overnight. The reaction was done by LC/MS andwas concentrated to an oil. It was then purified by flash columnchromatography using hexane/ethyl acetate 70/30 to give2-(2-methoxyethoxy)isoindoline-1,3-dione (2A, 5.19 g, 89.2% yield).ESI-MS: m/z 222.3 (M+H)⁺.

Step 2: 2-(2-methoxyethoxy) isoindoline-1,3-dione (5.18 g, 23.4 mmol)was dissolved in 50 mL of ethanol and hydrazine hydrate (22.7 mL, 468mmol). The solution was heated for 2 hours in a 80° C. oil bath. Thereaction was then cooled to room temperature and a solid precipitatedout. This solid was then filtered and the filtrate was concentrated andpurified on flash column chromatography using chloroform/methanol 98/2to give O-(2-methoxyethyl) hydroxylamine (2B, 0.866 g, 36.2% yield). ¹HNMR (400 MHz, MeOD) δ ppm 3.36 (s, 3H) 3.52-3.59 (m, 2H) 3.73-3.85 (m,2H).

B. Synthesis of O-(3-methoxypropyl)hydroxylamine(2D)

2-(3-Methoxypropoxy)isoindoline-1,3-dione (2C) was prepared from3-methoxypropan-1-ol and N-hydroxyphthalimide by a procedure analogousto Example 2A, Step 1 (3.71 g, 94.9% yield). ESI-MS: m/z 236.3 (M+H)⁺.

2C was deprotected as described in Example 2A, Step 2 to yieldO-(3-methoxypropyl)hydroxylamine (2D, 0.633 g, 38.1% yield). ¹H NMR (400MHz, MeOD) δ ppm 1.81 (t, J=6.32 Hz, 2H) 3.31 (s, 3H) 3.45 (t, J=6.32Hz, 2H) 3.70 (t, J=6.32 Hz, 2H). ESI-MS: m/z 106.4 (M+H)⁺.

C. Synthesis of tert-butyl 2-(aminooxy)ethylcarbamate (2F)

tert-Butyl 2-(1,3-dioxoisoindolin-2-yloxy)ethylcarbamate 2E was preparedwith quantitative yield from tert-butyl 2-hydroxyethylcarbamate andN-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1.ESI-MS: m/z 329.3 (M+Na)⁺.

2E was deprotected as previously described in 2A, Step 2 to givetert-butyl 2-(aminooxy)ethylcarbamate (2F, 1.26 g, 58% yield). ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 3.37 (q, J=5.31 Hz, 2H)3.62-3.85 (m, 2H) 4.90 (br. s., 1H) 5.47 (br. s., 2 H).

D. Synthesis of O-(pyridine-3-ylmethyl)hydroxylamine (2H)

Phthalimide-protected intermediate 2G was prepared frompyridin-3-ylmethanol and N-hydroxyphthalimide by a procedure analogousto Example 2A, Step 1 (3.22 g, 81.3% yield). ESI-MS: m/z 255.2 (M+H)⁺.

2G was deprotected as previously described in Example 2A, Step 2 to give0-(pyridine-3-ylmethyl)hydroxylamine (2H, 0.734 g, 69.2% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 4.71 (s, 2H) 7.44 (dd, J=7.83, 5.05 Hz, 1H)7.85 (d, J=7.83 Hz, 1H) 8.47 (dd, J=5.05, 1.26 Hz, 1H) 8.53 (d, J=2.27Hz, 1H). ESI-MS: m/z 125.3 (M+H)⁺.

2E. Synthesis of (R)-0((1,4-dioxan-2-yl)methyl)hydroxylamine (2M)

Step 1: 2-chloroethanol (34.8 g, 43.2 mmol) and boron trifluoridediethyl etherate (0.136 mL, 1.08 mmol) were dissolved in 20 mL of THFand cooled in an ice bath. (R)-(−)-epichlorohydrin (10.0 g, 10.8 mmol)in 10 mL of THF was added slowly through a syringe. After the addition,the ice bath was removed and the mixture was heated in a 45° C. oil bathfor 90 min at which time the reaction was complete. The reaction wasconcentrated in vacuo to give an oily crude product(R)-1-chloro-3-(2-chloroethoxy)propan-2-ol (2I, 16.2 g, 86.6% yield). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 3.56-3.71 (m, 6H) 3.85-3.92 (m, 3H).

Step 2: 2I (16.2 g, 93.6 mmol) was dissolved in 45 mL of THF and wascooled in an ice bath. Sodium hydroxide (9.36 g, 234 mmol) in 20 mL ofwater was added dropwise and the reaction was stirred in the ice bathfor 15 min, and at room temperature for 6 h. The reaction mixture wasdiluted with ethyl acetate and saturated sodium chloride solution. Theproduct was extracted into ethyl acetate layer three times. The combinedorganic layers was then washed with saturated sodium chloride solution,dried over sodium sulfate and concentrated to a crude oily product,(S)-2-((2-chloroethoxy)methyl)oxirane (2J, 11.1 g, 86.7% yield. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 2.57-2.72 (m, 2H) 2.76-2.89 (m, 2H)3.08-3.25 (m, 2H) 3.45 (dd, J=12.25, 5.68 Hz, 1H) 3.51-3.70 (m, 2H).

Step 3: 2J (11.1 g, 81.3 mmol) was dissolved in 50 mL of THF. Sodiumhydroxide (16.3 g, 406 mmol) in 50 mL of water was added and thereaction was heated in a 90° C. oil bath for one day. Despite the TLCshowing the reaction to be only half completed the product was extractedfrom the aqueous layer with ethyl acetate/THF, dichloromethane,n-butanol. The first two extractions contained product and the startingmaterial, which was later purified by flash column (ethyl acetate/hexane30/70). The latter extractions contained pure(5)-(1,4-dioxan-2-yl)methanol (2K, 1.98 g, 20.8% yield). ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 3.47 (t, J=9.98 Hz, 1H) 3.51-3.67 (m, 3H)3.67-3.87 (m, 5H).

Step 4: 2K (1.33 g, 11.2 mmol), N-hydroxyphthalimide (2.02 g, 12.4mmol), triphenylphosphine (3.25 g, 12.4 mmol) were dissolved in 30 mL ofdry THF and the mixture was cooled in an ice bath. Diisopropylazodicarboxylate (2.51 g, 12.4 mmol) in 5 mL of THF was added to theabove mixture dropwise. After the addition was complete, the ice bathwas removed and the reaction was stirred at room temp overnight. Nextday, the reaction was done. It was concentrated in vacuo to an oil andthen purified on flash column chromatography using ethyl acetate/hexane20/80 to give (R)-2-((1,4-dioxan-2-yl)methoxy)isoindoline-1,3-dione(2L). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.56 (t, J=10.74 Hz, 1H)3.60-3.85 (m, 4H) 3.92 (dd, J=11.75, 2.40 Hz, 1H) 4.05 (ddd, J=9.98,3.03, 2.91 Hz, 1H) 4.11-4.19 (m, 1H) 4.20-4.29 (m, 1H) 7.71-7.80 (m, 2H)7.81-7.91 (m, 2H).

Step 5: 2L (4.30 g, 12.4 mmol) was dissolved in 90 mL ofmethanol/dichloromethane 1/9 ratio. Hydrazine hydrate (1.67 mL, 22.4mmol) was added and the reaction was stirred at room temperature for 2 hat which time the deprotection was done. The precipitate byproduct wasfiltered, and the filtrate was concentrated down to an oil and thenpurified by flash column chromatography, using chloroform/methanol 99/1ratio to yield (R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M, 0.915g, 61.4% yield over 2 steps). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.41(t, J=10.86 Hz, 1H) 3.57-3.71 (m, 4H) 3.71-3.82 (m, 3H) 3.83-3.92 (m,1H) 5.55 (br. s., 2H).

F. Synthesis of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanamine (2O)

(S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanamine (2O) was prepared from(S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (2N) using a literatureprocedure (Tetrahedron Lett, 2005, 46, 5475-5478).

G. Synthesis of(R)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (2P)

The title compound was prepared according to Bailey et al., J. Med.Chem., 1991, 34, 51-65.

2H. Synthesis of(S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (2Q)

The title compound was prepared according to Bailey et al., J. Med.Chem., 1991, 34, 51-65.

2I. Synthesis of O-((2,2-dimethyl-1,3-dioxan-S-yl)methyl)hydroxylamine(2R)

The title compound was prepared according to Harnden et al, J. Med.Chem., 1990, 33, 187-196.

J. Synthesis of tert-butyl 2-(aminooxymethyl)morpholine-4-carboxylate(2T)

To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5g, 23 mmol) in CH₂Cl₂ (250 mL) was added 2-hydroxyisoindoline-1,3-dione(5.6 g, 34.5 mmol) and triphenylphosphine (15 g, 57.5 mmol). Theresultant mixture was cooled to 0° C. and diisopropyl azodicarboxylate(11.1 ml, 57.5 mmol) was slowly added dropwise with an addition funnelunder N₂ atmosphere. The reaction mixture was stirred at ambienttemperature for 48 h. To the reaction mixture H₂O (300 mL) was added andextracted with CH₂Cl₂. The organic layers were washed with brine. Driedover anhydrous MgSO₄, filtered and concentrated to provide clear oil,which was purified by flash chromatography (50% EtOAc-Hexane). Theresultant clear oily compound 2S was dissolved in CHCl₃:CH₃OH (50 ml).Hydrazine hydrate (25 mL, 0.25 mol) was added. The reaction mixture wasstirred at ambient temperature overnight. The resultant solid wasfiltered off and the filtrate concentrated under reduced pressure toprovide a clear oil, which was purified by flash chromatography (10%CH₃OH—CH₂Cl₂) to afford 3 g (56%, over two steps) of tert-butyl2-(aminooxymethyl)morpholine-4-carboxylate (2T) as a clear oil. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 3.46-3.62 (m, 2H) 3.61-3.79(m, 4H) 3.79-4.04 (m, 3H). [M+H] calc'd for C₁₀H₂₀N₂O₄, 233; found, 233.

K. Synthesis of(S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2W)

To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (14.2 mL,0.1 mol) in CH₂Cl₂ (250 mL) was added 2-hydroxyisoindoline-1,3-dione(16.3 g, 0.1 mol) and triphenylphosphine (39.3 g, 0.15 mol). Theresultant mixture was cooled to 0° C. and diisopropylazodicarboxylate(29.5 ml, 0.15 mol) was slowly added drop wise with an addition funnelunder N₂ atmosphere. The reaction mixture was stirred at ambienttemperature for 48 h. To the reaction mixture, H₂O (300 mL) was addedand the mixture extracted with CH₂Cl₂. The organic layers washed withbrine. Dried over anhydrous MgSO₄, filtered and concentrated to providea yellow oil, which was purified by flash chromatography (50%EtOAc-hexane) to yield 2U as a light yellow oil.

2U was dissolved in CH₂Cl₂ (250 ml) and cooled to 0° C. Hydrazinehydrate (25 mL, 0.25 mol) was added drop wise through an additionfunnel. The reaction mixture was stirred at ambient temperature overnight. The resultant solid was filtered off and the filtrateconcentrated under reduced pressure to provide a yellow oil, which waspurified by flash chromatography (70% EtOAc-hexane) to afford 7.2 g(45%, over two steps) of(S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2W) as apale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18(s, 3H), 1.53-1.71 (m, 2H), 3.53 (q, J=6.48 Hz, 2H), 3.79-3.89 (m, 1H),3.89-4.01 (m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated forC₂H₁₆NO₃, 162.11; found 162.0.

2L. Synthesis of(R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2X)

The title compound was prepared using the procedure described forExample 2K by using (R)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (4.28mL, 30 mmol), CH₂Cl₂ (100 mL), 2-hydroxyisoindoline-1,3-dione (4.9 g, 30mmol), triphenylphosphine (11.8 g, 45 mmol), diisopropylazodicarboxylate(8.8 ml, 45 mmol) and hydrazine hydrate (6.0 mL, 60 mmol) to afford 2.1g (43%, over two steps) of(R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (2X) as apale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 3H), 1.18(s, 3H), 1.53-1.71 (m, 2H), 3.53 (m, 2H), 3.79-3.89 (m, 1H), 3.89-4.01(m, 1H), 4.63-4.81 (m, 1H). MS (ES) [M+H] calculated for C₂H₁₆NO₃,162.11; found 162.0.

2M. Synthesis ofO-(((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine(2Y)

The title compound was prepared using the procedure described forExample 2K by using((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol(2.04 g, 10 mmol), CH₂Cl₂ (25 mL), 2-hydroxyisoindoline-1,3-dione (2.0g, 12 mmol), triphenylphosphine (4.0 g, 15 mmol),diisopropylazodicarboxylate (3.0 ml, 15 mmol) and hydrazine hydrate (2.0mL, 20 mmol) to afford 1.12 g of04(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine(2Y) (50%, over two steps) as a pale yellow oil. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.24 (s, 3H) 1.26 (s, 3H) 3.31 (s, 3H) 3.59-3.75 (m,2H) 4.44 (t, J=7.20 Hz, 1H) 4.56 (d, J=5.81 Hz, 1H) 4.67 (d, J=6.06 Hz,1H) 4.92-5.00 (m, 1H). MS (ES) [M+H] calculated for C₉H₁₈NO₅, 220.11;found 220.10.

Example 3 Chiral Separation of Racemic Mixture of2-Amino-742-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1F^(a) and 1F^(b))

Dihydroquinazolinone 1F (Example 1) was separated into its enantiomersby supercritical fluid chromatography (SFC) under the followingconditions:

-   -   Column: ChiralPak IA, 250×10 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: MeOH    -   Gradient Condition: 20% MeOH    -   Run Time: 12 min    -   Flow Rate: 20 mL/min    -   Injection volume: 800 μL

Total yield for the two enantiomers was 82% of the original amount ofthe racemic mixture. The yield for(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1F^(a)) was 45%. The yield for(S)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1F^(b)) was 37%.

Example 4 Chiral Separation of2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H^(a) and 1H^(b))

Dihydroquinazolinone 1H (Example 1) was separated into its enantiomers,1H^(a) and 1H^(b), by supercritical fluid chromatography (SFC) under thefollowing conditions:

-   -   Column: ChiralPak AD-H, 250×2 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: MeOH    -   Gradient condition: 30% MeOH    -   Run Time: 10 min    -   Flow Rate: 50 mL/min    -   Injection volume: 1000 μL

Total yield for the two enantiomers was 68% of the original amount ofthe racemic mixture. The yield for(R)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H^(a)) was 36%. The yield for(S)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1H^(b)) was 32%.

Example 5 Preparation of(E)-2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-methyl oxime (Compound 1)

Compound 1 was prepared as a white or off-white powder (90%) accordingto the procedure analogous to Example 1 using O-methylhydroxylamine. ¹HNMR (300 MHz, CDCl₃) δ ppm 2.58-2.68 (m, 5H), 2.78-2.88 (m, 3H), 5.02(s, 2H), 6.92 (dd, 1H), 7.17 (td, 1H), 7.29 (m, 1H), 7.40 (dd, 1H), 7.67(t, 1H), 8.25 (d, 1H). ESI-MS: m/z 396.1 (M+H)⁺.

Example 6 Chiral Separation of R and S Enantiomers of(E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-methyl oxime (Compound 2 and Compound 3)

Racemic mixture of Compound 1 was separated into its R and Senantiomers, Compound 2 and Compound 3, by SFC under the followingconditions:

-   -   Column: ChiralPak IA, 250×21 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (l)        -   B: EtOH    -   Gradient condition: 40% EtOH    -   Run time: 8 min    -   Flow Rate: 50 mL/min    -   Injection volume: 1000 μL,

Total yield for the two enantiomers was 45%. Yield for(R,E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-methyl oxime (1) was 23%. Yield for(S,E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(2) was 22%.

Example 7 Preparation of(E)-2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-allyl oxime (Compound 4)

Compound 4 was prepared as a white or off-white powder (90%) accordingto the procedure described in Example 1 using O-allylhydroxylamine. TheR and S enantiomers of Compound 4 may be obtained by SFC using aprocedure analogous to Example 6. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.58 (m,5H), 2.82 (m, 3H), 4.60 (s, 2H), 4.97 (s, 2H), 5.19-5.23 (m, 2H), 5.99(s, 1H), 6.92 (dd, 1H), 7.17 (td, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.69(m, 1H), 8.23 (s, 1H). ESI-MS: m/z 422.1 (M+H)⁺.

Example 8 Preparation of(E)-2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-tert-butyl oxime (Compound 5)

Compound 5 was prepared as a white or off-white powder (90%) accordingto a procedure described in Example 1 using O-tert-butylhydroxylamineThe R and S enantiomers of Compound 5 may be obtained by SFC using aprocedure analogous to Example 6. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.29 (s,9H), 2.61 (m, 4H), 2.82 (m, 3H), 4.96 (s, 2H), 6.94 (dd, 1H), 7.18 (td,1H), 7.30 (m, 1H), 7.43 (dd, 1H), 7.70 (m, 1H), 8.25 (s, 1H). ESI-MS:m/z 438.2 (M+H)⁺.

Example 9 Preparation of(E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-isobutyl oxime (Compound 6)

Compound 6 was prepared as a white or off-white powder (90%) accordingto the procedure described in Example 1 using O-isobutylhydroxylamineThe R and S enantiomers of Compound 6 may be obtained by SFC using aprocedure analogous to Example 6. ¹H NMR (300 MHz, CDCl₃) δ ppm 0.88 (m,6H), 1.67 (m, 1H), 2.29 (m, 5H), 2.59 (s, 3H), 3.86 (m, 2H), 5.03 (m,2H), 6.93 (dd, 1H), 7.19 (td, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.70 (m,1H), 8.24 (s, 1H). ESI-MS: m/z 438.2 (M+H)⁺.

Example 10 Preparation of(E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-benzyl oxime (Compound 7)

Compound 7 was prepared as a white or off-white powder (90%) accordingto the procedure described in Example 1 using O-benzylhydroxylamine TheR and S enantiomers of Compound 7 may be obtained by SFC using aprocedure analogous to Example 6. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.51 (s,3H), 2.60-2.81 (m, 4H), 4.97 (m, 2H), 5.12 (m, 2H), 6.91 (dd, 1H), 7.16(td, 1H), 7.26-7.39 (m, 7H), 7.65 (m, 1H), 8.25 (m, 1H). ESI-MS: m/z472.1 (M+H)⁺.

Example 11 Preparation of(E)-2-amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-phenyl oxime (Compound 8)

Compound 8 was prepared as a white or off-white powder (90%) accordingto the procedure described in Example 1 using O-phenylhydroxylamine. TheR and S enantiomers of Compound 8 may be obtained by SFC using aprocedure analogous to Example 6. ¹H NMR (300 MHz, CDCl₃) δ ppm2.65-3.07 (m, 7H), 6.04 (m, 2H), 6.96 (dd, 1H), 6.99 (t, 1H), 7.11-7.25(m, 3H), 7.26-7.35 (m, 3H), 7.44 (dd, 1H), 7.72 (m, 1H), 8.25 (m, 1H).ESI-MS: m/z 458.1 (M+H)⁺.

Example 12 Preparation of(E)-2-Amino-7-(4-fluoro-2-(2-fluoropyridin-3-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-4-nitrobenzyl oxime (Compound 9)

Compound 9 was prepared as a white or off-white powder (90%) accordingto the procedure described in Example 1 usingO-4-nitrobenzylhydroxylamine The R and S enantiomers of Compound 9 maybe obtained by SFC using a procedure analogous to Example 6. ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.44 (s, 3H), 2.64-6.80 (m, 3H), 3.20 (m, 2H), 5.28(s, 2H), 7.18 (dd, 1H), 7.38 (td, 1H), 7.45 (m, 1H), 7.60 (m, 2H), 7.72(dd, 1H), 7.99 (m, 1H), 8.25 (m, 3H). ESI-MS: m/z 517.2 (M+H)⁺.

Example 13 Preparation of2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A)

To a 5 mL microwave vial was added2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(1F (Example 1), 56 mg, 0.163 mmol, 1.0 eq.),2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (77mg, 0.325 mmol, 2.0 eq.), Pd(dppf)Cl₂ (11 mg, 0.013 mmol, 0.08 eq.), 2.0M aqueous K₂CO₃ (162 μL, 0.325 mmol, 2.0 eq.), and dimethylacetamide (2mL). The vial was sealed and heated in a microwave at 150° C. for 10min. LC/MS analysis showed the reaction was completed. The reactionmixture was filtered through Celite and purified via preparative-HPLC togive the product 13A as a white solid (33 mg, 55%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.54 (s, 3H) 2.62 (ddd, J=15.73, 3.03, 2.72 Hz, 1H)2.84-3.04 (m, 2H) 3.15-3.31 (m, 1H) 3.60-3.73 (m, 1H) 3.78 (s, 3H) 6.81(d, J=8.34 Hz, 1H) 7.15 (d, J=7.07 Hz, 1H) 7.22 (dd, J=9.60, 2.78 Hz,1H) 7.33 (td, J=8.59, 2.78 Hz, 1H) 7.55 (br. s., 2H) 7.71 (dd, J=8.84,5.81 Hz, 1H) 7.81 (dd, J=8.34, 7.33 Hz, 1H). ESI-MS: m/z 379.3 (M+H)⁺.

Example 14 Chiral Separation of R and S Enantiomers of2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A^(a) and 13A^(b))

Racemic mixture of Compound 13A was separated into its R and Senantiomers, Compound 13A^(a) and Compound 13A^(b), by SFC under thefollowing conditions:

-   -   Column: ChiralPak AD-H, 150×2.1 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: MeOH    -   Gradient condition: 30% MeOH    -   Run Time: 10 min    -   Flow Rate: 50 mL/min    -   Injection volume: 1000 μL

Total yield for the two enantiomers was 20%. Yield for(R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A^(a)) was 10%. Yield for(S)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A^(b)) was 10%.

Example 15 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-methoxyethyl oxime (Compound 10)

2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A (Example 13), 0.126 g, 0.33 mmol) and O-(2-methoxyethyl)hydroxylamine (0.121 g, 1.33 mmol) were dissolved in 2.2 mL of aceticacid/ethyl acetate 20/80 mol/mol ratio with a small amount ofp-toluenesulfonic acid monohydrate (0.0127 g, 0.0666 mmol). The reactionwas heated in a 80-85° C. oil bath overnight. The product was purifiedby preparatory LC/MS (35-50% CH₃CN in H₂O to give(E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-methoxyethyl oxime (10) as a TFA salt (0.067 g, 45% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.58 (s, 3 H) 2.60-2.69 (m, 1H) 2.73-2.83 (m,1H) 3.17-3.22 (m, 1H) 3.23 (s, 3H) 3.36 (dd, J=13.89, 2.02 Hz, 2H) 3.55(t, J=4.67 Hz, 2H) 3.74 (s, 3H) 4.17 (q, J=4.29 Hz, 2H) 6.79 (d, J=8.34Hz, 1H) 7.15 (d, J=7.33 Hz, 1H) 7.22 (dd, J=9.73, 2.65 Hz, 1H) 7.32 (td,J=8.53, 2.65 Hz, 1H) 7.69 (dd, J=8.59, 5.81 Hz, 1H) 7.78 (t, J=7.83 Hz,1H). ESI-MS: m/z 452.2 (M+H)⁺.

Example 16 Chiral Separation of R and S Enantiomers of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-methoxyethyl oxime (Compound 11 and Compound 12)

Racemic mixture of Compound 10 was separated into its R and Senantiomers, Compound 11 and Compound 12, by SFC under the followingconditions:

-   -   Column: ChiralPak AD-H, 250×21.2 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: EtOH    -   Gradient condition: 30% B    -   Run Time: 15 min    -   Flow Rate: 50 mL/min    -   Injection volume: 1000 μL,

Total yield for the two enantiomers was 68.1%. The yield for(R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-methoxyethyl oxime (11) was 33.6%. The yield for(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-methoxyethyl oxime (12) was 34.5%.

Example 17 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (Compound 13)

2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(13A (Example 13), 0.097 g, 0.256 mmol) andR—O-(2,2-dimethyl-1,3-dioxolan-4-yl-methyl)-hydroxylamine (0.113 g,0.769 mmol) were dissolved in 2.0 mL of dry pyridine. The reaction washeated in a 70-80° C. oil bath overnight. The reaction was poured intoan ice cold water beaker and the product precipitated out. It was thenfiltered and rinsed with H₂O to yield(E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime (17A) which was takenonto the next step without further purification. ESI-MS: m/z 508.4(M+H)⁺.

17A was deprotected with 80% acetic acid in water for 40 min, and theproduct was then purified by preparatory LC/MS (30-45% CH₃CN in H₂O togive(E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (13) as a TFA salt (0.108 g, 89.7%yield). ¹H NMR (400 MHz, MeOD) δ ppm 2.69-2.81 (m, 4H) 3.07 (br. s., 1H)3.15-3.25 (m, 2H) 3.36-3.63 (m, 3H) 3.81-3.86 (s, 3H) 3.87-3.97 (m, 1H)4.21 (m, 2H) 4.38 (m, 1H) 4.42-4.54 (m, 1H) 6.75 (d, J=8.34 Hz, 1H) 7.06(d, J=7.07 Hz, 1H) 7.09-7.17 (m, 1H) 7.17-7.27 (m, 1H) 7.57 (d, J=2.27Hz, 1H) 7.73 (t, J=7.96 Hz, 1H). ESI-MS: m/z 468.4 (M+H)⁺.

Example 18 Chiral Separation of R and S Enantiomers of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (Compound 14 and Compound 15)

Racemic mixture of Compound 13 was separated into its R and Senantiomers, Compound 14 and Compound 15 by SFC under the followingconditions:

-   -   Column: ChiralPak AD-H, 250×21.2 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: EtOH    -   Gradient condition: 20% B    -   Run Time: 25 min    -   Flow Rate: 20 mL/min    -   Injection volume: 1000 μL

Total yield for the two enantiomers was 16.2%. Yield for(R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (14) was 9.0%. Yield for(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (15) was 7.2%.

Example 19 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-tert-butoxyethyl oxime (Compound 16)

Compound 16 was prepared according to a procedure analogous to thatdescribed in Example 15 using O-(2-tert-butoxyethyl)hydroxylamine. Thecrude product was purified by preparatory LC/MS (45-55% CH₃CN in H₂O) togive Compound 16 as a TFA salt (0.0417 g, 51% yield). The R and Senantiomers of Compound 16 may be obtained by SFC using a procedureanalogous to Example 16. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (s, 9H)2.58 (s, 3H) 2.60-2.69 (m, 1H) 2.73-2.87 (m, 1H) 3.20 (dd, J=16.04,12.25 Hz, 1H) 3.28-3.44 (m, 2H) 3.52 (t, J=5.31 Hz, 2H) 3.75 (s, 3H)4.02-4.17 (m, 2H) 6.79 (d, J=8.08 Hz, 1H) 7.14 (d, J=7.33 Hz, 1H) 7.22(dd, J=9.73, 2.91 Hz, 1H) 7.32 (td, J=8.53, 2.91 Hz, 1H) 7.68 (dd,J=8.59, 5.81 Hz, 1H) 7.74-7.83 (m, 1H). ESI-MS: m/z 494.3 (M+H)⁺.

Example 20 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-3-methoxypropyl oxime (Compound 17)

Compound 17 was prepared according to a procedure analogous to thatdescribed in Example 15 except O-(3-methoxy-propyl)hydroxylamine wasused. The crude product was purified by preparatory LC/MS (50-65% CH₃CNin H₂O to give Compound 17 as a TFA salt (0.0428 g, 55.4% yield). The Rand S enantiomers of Compound 17 may be obtained by SFC using aprocedure analogous to Example 16. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.83(t, J=6.57 Hz, 2H) 2.51 (s, 3H) 2.55-2.66 (m, 1H) 2.67-2.79 (m, 1H)3.07-3.18 (m, 1H) 3.20 (s, 3H) 3.25-3.32 (m, 2H) 3.35 (t, J=6.32 Hz, 2H)3.74 (s, 3H) 4.08 (td, J=6.44, 1.77 Hz, 2H) 6.79 (d, J=8.08 Hz, 1H) 7.14(d, J=7.33 Hz, 1H) 7.21 (dd, J=9.60, 2.78 Hz, 1H) 7.31 (td, J=8.65, 2.91Hz, 1H) 7.68 (dd, J=8.84, 5.81 Hz, 1H) 7.74-7.84 (m, 1H). ESI-MS: m/z466.4 (M+H)⁺.

Example 21 Preparation of(E)-2-(2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylideneaminooxy)aceticacid (Compound 18)

Compound 18 was prepared using an analogous procedure described forExample 15 except that 2-(aminooxy)acetic acid was used. The crudeproduct was purified by preparatory LC/MS (40-60% CH₃CN in H₂O to giveCompound 18 as a TFA salt (0.0413 g, 70% yield). The R and S enantiomersof Compound 18 may be obtained by SFC using a procedure analogous toExample 16. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.42 (s, 3H) 2.66-2.79 (m,3H) 3.08-3.12 (m, 2H) 3.75 (s, 3H) 4.56 (d, J=1.77 Hz, 2H) 6.79 (d,J=8.08 Hz, 1H) 7.14 (d, J=7.07 Hz, 1H) 7.21 (dd, J=9.73, 2.91 Hz, 1H)7.26-7.36 (m, 1H) 7.66-7.73 (m, 1H) 7.74-7.83 (m, 1 H). ESI-MS: m/z452.3 (M+H)⁺.

Example 22 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO—(S)-2,3-dihydroxypropyl oxime (Compound 19)

Compound 19 was prepared using an analogous procedure described forExample 17 except thatS—O-(2,2-dimethyl-1,3-dioxolan-4-yl-methyl)-hydroxylamine was used. Thecrude product was purified by preparatory LC/MS (30-40% CH₃CN in H₂O togive Compound 19 as a TFA salt (0.0818 g, 70.5% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.52 (s, 3H) 2.62 (dd, J=17.94, 14.15 Hz, 1H) 2.75 (d,J=1.01 Hz, 1H) 3.07-3.19 (m, 1H) 3.27-3.38 (m, 5H) 3.68-3.73 (m, 2H)3.75 (s, 3H) 3.89-3.99 (m, 1H) 4.06 (ddd, J=10.86, 4.67, 3.16 Hz, 1H)6.79 (d, J=7.83 Hz, 1H) 7.14 (d, J=7.33 Hz, 1H) 7.21 (dd, J=9.60, 2.78Hz, 1H) 7.32 (td, J=8.59, 2.78 Hz, 1H) 7.69 (dd, J=8.72, 5.94 Hz, 1H)7.75-7.82 (m, 1H). ESI-MS: m/z 468.4 (M+H)⁺.

Example 23 Chiral Separation of R and S Enantiomers of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (Compound 20 and Compound 21)

Racemic mixture of Compound 19 was separated into its R and Senantiomers, Compound 20 and Compound 21 by SFC under the followingconditions:

-   -   Column: ChiralPak AD-H, 250×10 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: MeOH    -   Gradient condition: 25% B    -   Run Time: 15 min    -   Flow Rate: 20 mL/min    -   Injection volume: 1000 μL,

Total yield for the two enantiomers was 34.7%. Yield for(R,E)-(E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydr oxypr opyl oxime (2O) was 14.1%. Yield for(S,E)-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (21) was 20.6%.

Example 24 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-aminoethyl oxime (Compound 22)

Compound 22 was prepared using an analogous procedure described forExample 15 except that tert-butyl 2-(aminooxy)ethylcarbamate was used.The final Boc-deprotection was effected by treatment of 24A (0.180 g,0.019 mmol) with 20% TFA/CH₂Cl₂ for 10 min. The reaction was completedas judged by LC/MS. The reaction was concentrated in vacuo and theresidue was purified by preparatory LC/MS (25-35% CH₃CN in H₂O) to giveproduct 22 as a TFA salt (0.0625 g, 75.3% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.52 (s, 3H) 2.62-2.74 (m, 1H) 2.76-2.90 (m, 1H)2.99-3.18 (m, 3H) 3.32 (d, J=12.38 Hz, 2H) 3.75 (s, 3H) 4.20 (t, J=5.05Hz, 2H) 6.80 (d, J=8.08 Hz, 1H) 7.14 (d, J=7.33 Hz, 1H) 7.23 (dd,J=9.73, 2.91 Hz, 1H) 7.33 (td, J=8.53, 2.91 Hz, 1H) 7.69 (dd, J=8.84,5.81 Hz, 1H) 7.74-7.86 (m, 1H). ESI-MS: m/z 437.4 (M+H)⁺.

Example 25 Chiral Separation of R and S Enantiomers of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-aminoethyl oxime (Compound 23 and Compound 24)

Racemic mixture of Compound 22 was separated into its R and Senantiomers, Compound 23 and Compound 24, by SFC under the followingconditions:

-   -   Column: ChiralPak AD-H, 250×10 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: MeOH+10 mM NH₄OAc    -   Gradient condition: 30% B    -   Run Time: 8 min    -   Flow Rate: 20 mL/min    -   Injection volume: 75 μL

Total yield for the two enantiomers was 23%. Yield for(R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-aminoethyl oxime (23) was 9.2%. Yield for(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-aminoethyl oxime (24) was 13.9%.

Example 26 Preparation of (E) and (Z) Isomers of2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-pyridin-3-ylmethyl oxime (Compound 25 and Compound 26)

The racemic mixture which contained Compounds 25 and 26 was prepared bya procedure analogous to that described in Example 15 except thatO-(pyridin-3-ylmethyl)hydroxylamine was used. The crude product waspurified by preparatory LC/MS (25-40% CH₃CN in H₂O to give products asTFA salt. The E and Z isomers were separated by preparatory LC/MS(25%-40% CH₃CN in H₂O) with a total yield of 71.6%.

Yield for (E)2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-pyridin-3-ylmethyl oxime (25) was 0.0398 g, 50.2%. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.37 (s, 3H) 2.58-2.83 (m, 2H) 3.12 (dd, J=16.04, 12.25Hz, 1H) 3.32 (dd, J=13.26, 3.92 Hz, 2H) 3.67 (s, 3H) 5.20 (d, J=3.03 Hz,2H) 6.78 (d, J=8.34 Hz, 1H) 7.14 (d, J=7.33 Hz, 1H) 7.21 (dd, J=9.60,2.78 Hz, 1H) 7.31 (td, J=8.53, 2.91 Hz, 1H) 7.63-7.73 (m, 2H) 7.78 (t,J=7.83 Hz, 1H) 8.11 (d, J=7.58 Hz, 1H) 8.68 (br. s., 1H) 8.74 (s, 1H).ESI-MS: m/z 485.4 (M+H)⁺.

Yield for (Z)2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-pyridin-3-ylmethyl oxime (26) was 0.017 g, 21.4%. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.12 (s, 3H) 2.63-2.71 (m, 1H) 2.72-3.00 (m, 4H) 3.80 (s,3H) 5.11 (s, 2H) 6.83 (d, J=8.34 Hz, 1H) 7.12 (d, J=7.33 Hz, 1H) 7.18(dd, J=9.73, 2.91 Hz, 1H) 7.26 (td, J=8.53, 2.91 Hz, 1H) 7.57 (ddd,J=13.71, 8.40, 5.43 Hz, 2H) 7.73-7.88 (m, 1H) 7.96 (d, J=7.33 Hz, 1H)8.64 (s, 1H) 8.79 (br. s., 1H). ESI-MS: m/z 485.4 (M+H)⁺.

Example 27 Preparation of(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-3-hydroxy-2-(hydroxymethyl)propyl oxime (Compound 27) and ChiralSeparation of Enantiomers

Compound 27 was prepared by a procedure analogous to that described inExample 17 except thatO-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)hydroxylamine was used. Thecrude product was purified by preparatory LC/MS (35-40% CH₃CN in H₂O togive Compound 17 as a TFA salt (0.109 g, 42.9% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.89 (m, 1H) 2.47 (s, 3 H) 2.54 (m, 1H) 2.67 (br. s., 2H)3.07 (d, J=15.66 Hz, 1H) 3.25 (m, 1H) 3.41 (q, J=5.31 Hz, 4 H) 3.75 (s,3H) 4.03 (d, J=8.00 Hz, 2H) 4.39 (q, J=4.97 Hz, 2H) 6.79 (d, J=8.34 Hz,1H) 7.13 (d, J=7.33 Hz, 1H) 7.20 (dd, J=9.60, 2.53 Hz, 1H) 7.25-7.35 (m,1H) 7.68 (dd, J=8.59, 5.81 Hz, 1H) 7.74-7.83 (m, 1H). ESI-MS: m/z 482.4(M+H)⁺.

The R and S enantiomers of Compound 27 was separated by SFC under thefollowing conditions:

-   -   Column: ChiralPak AD, 250×10 mm, 5 μm    -   Mobile Phase:        -   A: CO₂ (1)        -   B: IPOH    -   Gradient condition: 40% B    -   Run Time: 12 min    -   Flow Rate: 15 mL/min    -   Injection volume: 500 μL

Total yield for the two enantiomers was 50.3%. Yield for(R,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-3-hydroxy-2-(hydroxymethyl)propyl oxime (28) was 27.9%. Yield for(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-3-hydroxy-2-(hydroxymethyl)propyl oxime (29) was 22.4%.

Example 28 Preparation of(E)-2-(2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylidene)hydrazinecarboximidamide(Compound 30)

The ketone 13A ((Example 13) 0.100 g), aminoguanidine hydrochloride(0.0876 g, 3 eq.) and 5N HCl (5 eq.) were dissolved in ethanol and washeated in a 90° C. oil bath for 2 hours. The crude product was thenpurified by preparatory LC/MS (40-45% CH₃CN in H₂O to give(E)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-ylidene)hydrazinecarboximidamide (30) as a TFA salt(0.0617 g, 53.6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.64 (s, 3H)2.70-2.82 (m, 2H) 3.15-3.33 (m, 2H) 3.48 (br. s., 1 H) 3.73 (s, 3H) 6.80(d, J=8.34 Hz, 1H) 7.17 (d, J=7.33 Hz, 1H) 7.25 (dd, J=9.73, 2.65 Hz, 1H) 7.33-7.40 (m, 1H) 7.74-7.86 (m, 2H) 10.74 (s, 1H). ESI-MS: m/z 435.4(M+H)⁺.

Example 29 Preparation of(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 31)

Compound 31 was prepared using an analogous procedure described forExample 17 except that(S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine was used.The crude product was purified by preparatory LC/MS (CH₃CN in H₂O togive(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime as a TFA salt (31, 4.5 mg, 7.1% yield).¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.37 (m, 1H) 2.46-2.64 (m, 4H)2.81-2.99 (m, 2H) 3.25-3.53 (m, 3H) 3.58-3.66 (m, 1H) 3.77-3.96 (m, 4H)4.16-4.38 (m, 3H) 5.18 (br. s., 2H) 6.66-6.78 (m, 1H) 6.95 (dd, J=7.33,4.29 Hz, 1H) 7.02-7.22 (m, 2H) 7.31-7.44 (m, 1H) 7.55-7.68 (m, 1H).[M+H] calc'd for C₂₅H₂₈FN₅O₄, 482; found, 482.

Example 30 Preparation of2-Amino-7-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(30H)

A. Synthesis of 3-(6-methoxypyridin-2-yOthiophene-2-earbaldehyde (30C)

To a 500 mL flask was added 2-formylthiophene-3-boronic acid (30A, 5.00g, 32.1 mmol, 1.0 eq.), 2-bromo-6-methoxypyridine (30B, 6.03 g, 32.1mmol, 1.0 eq.), toluene (100 mL), EtOH (100 mL), aqueous sodiumcarbonate (2N, 32 ml, 64 mmol, 2.0 eq.), and Pd(dppf)Cl₂ (1.17 g, 1.6mmol, 0.05 eq.). The reaction was stirred overnight at 90° C. Thereaction was cooled and saturated aqueous NaCl (100 mL) was added andthe mixture was stirred for 20 min. The reaction mixture was extractedwith EtOAc (2×100 mL) and the resulting organic layers were combined andpassed through a Celite pad to remove residual Pd. The organic phaseswere washed with a succession of H₂O (100 mL) and saturated aqueous NaCl(100 mL) and then dried over anhydrous Na₂SO₄, filtered, andconcentrated to give a bubbly brown solid that was used in the next stepwithout further purification (6.2 g, 88%). ESI-MS: m/z 220.2 (M+H)⁺.

B. Synthesis of(E)-4-(3-(6-methoxypyridin-2-yOthiophen-2-yObut-3-en-2-one (30D)

To a 500 mL recovery flask was added3-(6-methoxypyridin-2-yl)thiophene-2-carbaldehyde (30C, 6.2 g, 28.3mmol, 1.0 eq.), acetone (16.6 mL, 226 mmol, 8.0 eq.), and H₂O (130 mL).Upon cooling to 0° C. in an ice bath, aqueous NaOH (5N, 6.2 mL, 31.1mmol, 1.1 eq.) was added. The reaction mixture was stirred overnightwhile warming to room temperature. LC/MS monitoring showed the reactionto be −60% complete, so additional aqueous NaOH (5N, 1 mL, 5.0 mmol,0.18 eq.) was added. After stirring for an additional 6 h the reactionwas complete by LC/MS. The reaction mixture was neutralized with 3Naqueous HCl to a pH-8. The mixture was extracted with EtOAc (3×100 mL).The organic phases were combined and washed with saturated aqueous NaCl(100 mL). The combined aqueous phases were extracted with EtOAc (100mL). The organic phases were combined and dried over anhydrous Na₂SO₄,filtered, and concentrated to give a black solid. The residue waspurified via flash chromatography (60% CH₂Cl₂/Hex to 100% CH₂Cl₂) togive a yellow solid 30D (4.8 g, 67%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.29 (s, 3H) 3.96 (s, 3H) 6.59 (d, J=15.92 Hz, 1H) 6.84 (d, J=8.34 Hz,1H) 7.41 (d, J=7.58 Hz, 1H) 7.60 (d, J=5.31 Hz, 1H) 7.75-7.88 (m, 2H)8.71 (d, J=15.92 Hz, 1H). ESI-MS: m/z 260.3 (M+H)⁺.

C. Synthesis of3-hydroxy-5-(3-(6-methoxypyridin-2-yOthiophen-2-Acyclohex-2-enone (30F)

To a 200 mL recovery flask was added(E)-4-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)but-3-en-2-one (30D, 4.81g, 18.6 mmol, 1.0 eq.), MeOH (100 mL), and dimethylmalonate (30E, 2.13mL, 18.6 mmol, 1.0 eq.). NaOMe (30% wt in MeOH, 3.66 mL, 19.5 mmol, 1.05eq.) was added and the reaction mixture was stirred overnight at reflux.LC/MS analysis showed the desired intermediate and the mixture wasconcentrated and then taken up in 1N aqueous NaOH (100 mL) and refluxedfor 1 h. The reaction was then cooled to 0° C. in an ice bath andacidified with 1N HCl until acidic. The reaction mixture was thenstirred at 80° C. for 1 h. After cooling to room temperature, EtOAc (200mL) was added and the organic phase was washed with saturated aqueousNaCl (100 mL). The combined aqueous phases were extracted with EtOAc(100 mL). The combined organic phases were dried over anhydrous Na₂SO₄,filtered, and concentrated to give a foamy brown solid 30F that wastaken on to the next step without further purification. (4.9 g, 88%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 2.67 (m, 3H) 3.79 (s, 3H) 4.54-4.70 (m, 1H)5.30 (s, 1H) 6.73 (d, J=8.08 Hz, 1H) 7.31 (d, J=7.33 Hz, 1H) 7.39-7.54(m, 2H) 7.76 (t, J=7.83 Hz, 1H). ESI-MS: m/z 302.3 (M+H)⁺.

D. Synthesis of2-acetyl-3-hydroxy-5-(3-(6-methoxypyridin-2-yOthiophen-2-yl)cyclohex-2-enone(30G)

To a 200 mL recovery flask was added3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone(30F, 4.9 g, 16.3 mmol, 1.0 eq.), CH₂Cl₂ (100 mL), acetic anhydride(2.15 g, 21.1 mmol, 1.3 eq.), Et₃N (6.8 mL, 48.8 mmol, 3.0 eq.), andDMAP (catalytic). The reaction mixture was stirred overnight at roomtemperature whereupon LC/MS showed two signals corresponding to M+H=344.Additional acetic anhydride (0.5 mL, 5.3 mmol, 0.32 eq.) was added andthe reaction mixture was heated for 6 h at 40° C. LC/MS analysis showedthe reaction to be complete whereupon the mixture was concentrated to asolid and purified via flash chromatography (70% CH₂Cl₂/Hex to 100%CH₂Cl₂) to yield a dark orange solid 30G (1.72 g, 31%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.52-2.57 (m, 3H) 2.83 (m, 2 H) 3.09 (m, 2H) 3.78 (s, 3H)4.68 (m, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.32 (d, J=7.33 Hz, 1H) 7.41-7.47(m, 1H) 7.51 (d, J=5.31 Hz, 1H) 7.76 (t, J=7.96 Hz, 1H). ESI-MS: m/z344.3 (M+H)⁺.

E. Synthesis of2-amino-7-(3-(6-methoxypyridin-2-yOthiophen-2-yl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one(30H)

To a 150 mL pressure vessel was added2-acetyl-3-hydroxy-5-(3-(6-methoxypyridin-2-yl)thiophen-2-yl)cyclohex-2-enone(30G, 1.72 g, 5.01 mmol, 1.0 eq.), EtOH (50 mL), pyrrolidine (2.13 g,30.1 mmol, 6.0 eq.), guanidine hydrochloride (1.44 g, 15 mmol, 3.0 eq.).The vessel was sealed and heated overnight at 100° C. LC/MS analysisshowed the reaction to be complete whereupon the reaction mixture wasconcentrated and the residue was taken up in 20% EtOAc/CH₂Cl₂. Aninsoluble solid proving not to be product was filtered off The remainingfiltrate was purified via column chromatography (20% EtOAc/CH₂Cl₂ to 70%EtOAc/CH₂Cl₂) to yield the product 30H as a light gray solid (270 mg,15%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.55 (s, 3H) 2.76-2.95 (m, 2H)3.02-3.22 (m, 2H) 3.70 (s, 3H) 4.62-4.77 (m, 1H) 6.72 (d, J=8.34 Hz, 1H)7.31 (d, J=7.58 Hz, 1H) 7.41-7.54 (m, 4H) 7.75 (t, J=7.83 Hz, 1H).ESI-MS: m/z 367.3 (M+H)⁺.

Example 31 Preparation of(R)-2-Amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine-5-thione(311) and(R)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one(31J)

A. Synthesis of (S)-2-methyl-propane-2-sulfinic acid1-(2-bromo-4-fluoro-phenyl)-methyl-(E)-ylideneamide (31 C)

(S)-tert-Butanesulfinimide (31A, 9.9 g, 81.6 mmol),2-bromo-4-fluoro-benzaldehyde (31B, 15.5 g, 76 mmol), and titaniumtetraethoxide (34 mL) were charged into a 500 mL round bottom flaskcontaining THF (dry, 50 mL). The reaction was allowed to stir at ambienttemperature for 2 h which was deemed complete by LCMS. EtOAc (200 mL),brine (150 mL), and celite was added and stir for 1 h. The heterogeneousmixture was filtered through a pad of celite, and washed with EtOAc. Theorganic layer was washed with brine and dried (Na₂SO₄), thenconcentrated in vacuo to afford the product 31C as viscous oil (23.3 g,99% yield). 31C was used in the next step without further purification.

B. Synthesis of (R)-3-amino-3-(2-bromo-4-fluoro-phenyl)-propionic acidethyl ester (31D)

A 500 mL 3-necked flask fitted with an overhead stirrer, a 150 mLaddition funnel and a reflux condenser, was charged with THF (dry, 150mL), Zn (74.5 g, 1.14 mol, 10 μm particle size) and CuCl (11.3 g, 114mmol) under N₂ atmosphere. The heterogeneous mixture was refluxed for 1h while stirring vigorously. After cooling to ambient temperature, ethylbromoacetate (12.61 mL, 114 mmol) was added and the reaction was held at50° C. for 1 h then cooled to 0° C. 31C (23.3 g, 76 mmol) in THF (dry,80 mL) was added via the addition funnel over 10 min. The reaction washeld at 0° C. for 4 h then warmed to ambient temp and stirred for 12 h.The heterogeneous mixture was filtered through a pad of celite andwashed with EtOAc. The organic layer was washed with citric acid (1M),NaHCO₃, brine, dried over Na₂SO₄ and concentrated in vacuo to give 24.3g of light yellow solid. The solid was then taken up in diethyl ether(200 mL), EtOH (5 mL), and HCl (38 mL, 4M in dioxane). After 30 min theproduct 31D precipitated and was filtered, the solid washed with excessdiethyl ether dried under high vacuum to afford the (3-amino ester HClsalt in good yield (15.6 g, 47.7 mmol, 63%). The mother liquor containedan additional 1.9 g (6.5 mmol, 8.5%) of freebase after neutralizationand column chromatography (1-5%, MeOH in DCM). ESI-MS: m/z 290.01 (MH⁺).

C. Synthesis of(R)-3-(2-bromo-4-fluoro-phenyl)-3-(3-oxo-butylylamino)-propionic acidethyl ester (31F)

A 500 mL round-bottom flask charged with 31D (13.3 g, 41 mmol) in 200 mLof DCM and TEA (22.8 mL, 3 equiv.) was added diketene (31E, 8.81 mL, 50%in DCM). The reaction was stirred at ambient temperature untilcompletion (2 h, determined by LCMS). The reaction mixture was washedwith 1 N NaHSO₄, brine, dried over Na₂SO₄ and concentrated in vacuo toafford Compound 31F as a yellow solid (15.3 g, 99%). ESI-MS: m/z 374.0(MH⁺).

D. Synthesis of(R,E)-6-(2-bromo-4-fluorophenyl)-3-(1-hydroxyethylidene)piperidine-2,4-dione(31G)

To a flask containing 30 mL dry MeOH was added sodium metal (1.00 g,43.5 mmol, 3.4 eq.). The mixture was stirred vigorously until sodium isdissolved. To a pressure vessel containing 31F (4.81 g, 12.9 mmol, 1.0eq.) in MeOH (50 mL) was added the freshly prepared NaOMe solution. Thepressure vessel was sealed and heated at 100° C. overnight. LC/MSanalysis showed the product as the major signal. The reaction mixturewas concentrated and then diluted with methylene chloride (500 mL) andaqueous 1 N NH₄Cl (100 mL). The organic phase was further washed withaqueous 1 N NH₄Cl (100 mL) and saturated aqueous NaCl (100 mL). Thecombined aqueous phases were extracted with methylene chloride (2×75mL). The combined organic phases were dried over anhydrous Na₂SO₄,filtered, and concentrated to give a dark yellow solid 31G which wasdeemed pure enough to take on to the next reaction without furtherpurification (2.05 g, 49%). ESI-MS: m/z 328.2 (M+H)⁺

E. Synthesis of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-4]pyrimidin-5(6H)-one(31H)

A microwave vial charged with acetylguanidine (800 mg, 7.9 mmol) wasadded pyrrolidine (3.25 mL, 39 mmol), 5 mL of EtOH and 31G (1.3 g, 3.9mmol). The mixture was heated in a microwave at 160° C. for 10 min. Thereaction mixture was diluted with EtOAc (50 mL) and washed with 1MNaHSO₄ (40 mL×2), brine, dried over Na₂SO₄, concentrated in vacuo. Theresulting solid was purified by column chromatography (2-5% MeOH in DCMgradient) to give the product 31H as a light yellow crystalline solid(989 mg, 72%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.61 (s, 3H) 2.83 (dd,J=16.29, 5.94 Hz, 1H) 3.22 (dd, J=16.42, 6.06 Hz, 1H) 4.84-5.06 (m, 1H)7.11 (br. s., 2H) 7.19-7.40 (m, 2H) 7.61 (dd, J=8.59, 2.53 Hz, 1H) 7.98(d, J=3.28 Hz, 4H). ESI-MS: m/z 351.0 (MH⁺).

F. Synthesis of(R)-2-Amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-4]pyrimidine-5-thione(311)

A 4 mL vial charged with 31H and 2 mL of DME was added Davy reagent (250mg, 0.71 mmol). The mixture was heated to 100° C. for 20 min. The crudemixture was directly charged into a 12 g silica column and eluted (2-4%MeOH in DCM) to give the thiolactam 31I in modest yield (134 mg, 52%).ESI-MS: m/z 367.0 (MH⁺).

G. Synthesis of(R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-Aphenyl)-4-methyl-7,8-dihydropyrido[4,3-4]pyrimidin-5(6H)-one(31J)

To a 5 mL microwave vial was added 31H (700 mg, 1.99 mmol, 1.0 eq.),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.43 g, 4.78mmol, 2.4 eq.), Pd(dppf)Cl₂ (73 mg, 0.0997 mmol, 0.05 eq.), K₂CO₃ (826mg, 5.98 mmol, 3.0 eq.), and dimethylacetamide (10 mL). The vial wassealed and heated in a microwave at 110° C. for 30 min. LC/MS analysisshowed the reaction was complete. The reaction mixture was diluted withmethanol, filtered, and purified via preparative-HPLC to give theproduct 31J as a white solid (618 mg, 81.7% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.58 (s, 3H) 2.80-2.95 (m, 1H) 3.08-3.22 (m, 1H) 3.86 (s,3H) 5.15 (br. s., 1H) 6.86 (d, J=7.58 Hz, 1H) 7.18 (d, J=6.82 Hz, 1 H)7.23-7.33 (m, 2H) 7.55 (dd, J=8.59, 5.81 Hz, 1H) 7.84 (dd, J=8.34, 7.33Hz, 2H). ESI-MS: m/z 380.2 (M+H)⁺.

Example 32 Preparation of(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime (Compound 32) and(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (Compound 33)

A 4 mL vial charged with(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidine-5-thione(31I (Example 31), 107 mg, 0.28 mmol),(R)-0-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (247 mg,1.68 mmol), and dioxane (2 mL) was heated to 100° C. for 12 h. The crudemixture was purified by preparative reverse phase HPLC (10-70% H₂O—AcCN,0.035% TFA) to afford the product(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime (32A) in modest yield(40 mg, 30% yield). ESI-MS: m/z 480.1 (M+H)⁺.

To a vial containing 32A (40 mg, 0.083 mmol),2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (58mg, 0.25 mmol), Na₂CO₃ (0.5 mL, 1.0 mmol), Pd(dppf)₂Cl₂ (3.4 mg, 0.004mmol) and DMA (0.5 mL) was heated to 130° C. for 20 min in themicrowave. The resultant crude mixture was diluted with EtOAc, andwashed with H₂O, brine, dried over Na₂SO₄, and concentrated in vacuo toyield(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl oxime (32) afterreverse-phase preparative HPLC (16 mg, 39% yield, 10-70% H₂O—AcCN,0.035% TFA). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 3H) 1.41 (s,3H) 2.85 (s, 3H) 3.15 (dd, J=17.05, 10.48 Hz, 1H) 3.46 (dd, J=17.18,3.79 Hz, 1H) 3.70-3.80 (m, 1H) 3.88 (s, 3H) 3.99-4.17 (m, 3H) 4.36-4.49(m, 1H) 4.90 (dd, J=10.36, 3.54 Hz, 1H) 4.30-5.10 (br, 2H) 5.80 (br, 1H)6.76 (d, J=8.34 Hz, 1H) 7.02 (d, J=7.33 Hz, 1H) 7.10-7.24 (m, 2H) 7.60(dd, J=8.59, 5.56 Hz, 1H) 7.68 (t, J=7.83 Hz, 1H). ESI-MS: m/z 509.4(M+H)⁺.

Compound 32 was taken up in AcOH—H₂O (1 mL, 5:1) and heated to 80° C.for 30 min; the excess AcOH was removed under vacuum. The crude productwas then purified by reverse phase preparative HPLC to yield(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime (33, 12 mg, 20-75% H₂O—AcCN, 10 mM(NH₄)₂CO₂). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.48 (s, 3H) 2.81 (dd,J=16.17, 7.83 Hz, 1H) 3.04 (dd, J=16.17, 4.80 Hz, 1H) 3.28-3.41 (m, 2H)3.66-3.76 (m, 1H) 3.78-3.84 (m, 1H) 3.9 (s, 3H) 3.89-3.97 (m, 1H) 4.51(t, J=5.68 Hz, 1H) 4.64 (d, J=4.80 Hz, 1H) 4.94-5.05 (m, 1H) 6.48 (s,1H) 6.79 (s, 2H) 6.85 (d, J=8.34 Hz, 1H) 7.18 (d, J=7.33 Hz, 1H)7.23-7.35 (m, 2H) 7.53 (dd, J=8.59, 5.81 Hz, 1H) 7.84 (t, J=7.83 Hz,1H). ESI-MS: m/z 469.2 (M+H)⁺.

Example 33 Preparation of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-2,3-dihydroxypropyl oxime (Compound 34)

The title compound was prepared by the procedure of Example 32 exceptthat (S)-0-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine wasused. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (s, 3H) 2.97-3.14 (m,1H) 3.16-3.28 (m, 1H) 3.55-3.68 (m, 1H) 3.68-3.76 (m, 3H) 3.90 (s, 3H)3.97-4.20 (m, 3H) 4.90 (dd, J=10.23, 3.92 Hz, 1H) 5.26 (br. s., 2H) 5.83(s, 1H) 6.74 (d, J=8.34 Hz, 1H) 7.00 (d, J=7.07 Hz, 1H) 7.07-7.22 (m,2H) 7.52-7.76 (m, 2H). ESI-MS: m/z 469.2 (M+H⁺).

Example 34 Synthesis of(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-3-hydroxy-2-(hydroxymethyl)propyl oxime (Compound 35)

The title compound 35 was prepared by a procedure analogous to thatdisclosed in Example 32 exceptO-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)hydroxylamine was used. Thecrude product was purified by reverse phase HPLC (5 mg, 20-75% H₂O—AcCN,10 mM (NH₄)₂CO₂) to afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-3-hydroxy-2-(hydroxymethyl)propyl oxime (33, 5 mg, 2.9% yield). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.88-2.05 (m, 1H) 2.53 (s, 3H) 2.81 (dd,J=16.17, 7.33 Hz, 1H) 3.03 (dd, J=16.04, 4.93 Hz, 1H) 3.42-3.50 (m, 4H)3.86 (s, 3H) 3.93 (dd, J=6.32, 2.53 Hz, 2H) 4.29-4.39 (m, 2H) 5.00-5.10(m, 1H) 6.31 (s, 1H) 6.76 (s, 2 H) 6.85 (d, J=8.34 Hz, 1H) 7.19 (d,J=7.33 Hz, 1H) 7.21-7.32 (m, 2H) 7.49 (dd, J=8.59, 5.81 Hz, 1H) 7.84 (t,J=7.83 Hz, 1H). ESI-MS: m/z 483.3 (M+H⁺).

Example 35 Synthesis of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 36) and(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 37)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(311,100 mg, 0.3 mmol),(S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine (194 mg,1.2 mmol), Hg(OAc)₂ (192 mg, 0.6 mmol) and anhydrous toluene (2 mL) washeated at 100° C. for 1 h. LCMS shows completion of the reaction. Themixture was cooled, filtered through celite and washed with ethylacetate. Filtrate concentrated and the resulting oily residue waspurified by preparative LCMS to afford(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (35A, 87 mg, 65%) asa pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.35 (s, 3H) 1.40(s, 3H) 2.01 (qd, J=6.32, 3.03 Hz, 2 H) 2.76 (s, 3H) 2.95 (dd, J=16.42,8.84 Hz, 1H) 3.18 (dd, J=17.18, 5.05 Hz, 1H) 3.56-3.62 (m, 1H) 4.09 (dd,J=7.96, 5.94 Hz, 1H) 4.16-4.28 (m, 2H) 4.98 (ddd, J=8.78, 4.61, 1.52 Hz,1 H) 7.07 (td, J=8.21, 2.53 Hz, 1H) 7.34 (dd, J=8.08, 2.53 Hz, 1H) 7.68(dd, J=12.00, 6.95 Hz, 1 H). MS (ES) [M+H] calculated forC_(2i)H₂₆BrFN₅O₃, 494.11; found 494.00.

A mixture of the above compounds (83.0 mg, 0.17 mmol),2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80.0mg, 0.34 mmol), Pd(dppf)₂Cl₂ (14 mg, 0.017 mmol), 2N Na₂CO₃ (0.42 mL,0.85 mmol) in DMA (2 mL) was degassed with N₂ and heated at 80° C. for2.5 h. LCMS shows 1:1 mixture of starting material and product. Thereaction mixture was cooled, filtered through celite and washed with 1:1MeOH—CH₂Cl₂. The filtrate was concentrated and the residue was dissolvedin 4:1 mixture of AcOH—H₂O and heated at 80° C. for 30 minutes. Solventremoved under reduced pressure and the residue was purified bypreparative HPLC (basic mode) to afford Compounds 36 and 37.

Compound 36:(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (36, 8.0 mg). ¹H NMR (400 MHz,METHANOL-d₄) d 1.68-1.80 (dddd, J=14.31, 8.75, 5.65, 5.65 Hz, 1H), 2.02(dddd, J=14.24, 7.74, 6.44, 3.92 Hz, 1H), 2.85 (s, 3H), 3.18 (dd,J=16.93, 6.57 Hz, 1H), 3.37 (dd, J=16.80, 5.43 Hz, 1H), 3.43-3.55 (m,2H), 3.72-3.82 (m, 1H), 4.18-4.31 (m, 2 H), 5.14 (t, J=5.94 Hz, 1H),7.15 (td, J=8.40, 2.65 Hz, 1H), 7.39 (dd, J=8.84, 5.81 Hz, 1H), 7.46(dd, J=8.34, 2.78 Hz, 1H). MS (ES) [M+H] calculated for C₁₈H₂₂BrFN₅O₃,454.29; found 454.20).

Compound 37:(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (37, 8.0 mg). ¹H NMR (400 MHz,CHLOROFORM-d) δ 1.53-1.58 (m, 1H) 1.69-1.73 (m, 1H) 2.46 (s, 3H)2.79-2.87 (m, 1H) 2.93-2.98 (m, 1H) 3.22-3.28 (m, 1H) 3.35-3.38 (m, 1H)3.54-3.60 (m, 1H) 3.70 (s, 3H) 3.94-4.00 (m, 2H) 4.69 (ddd, J=10.23,3.03, 2.91 Hz, 1H) 6.55 (dd, J=8.34, 2.53 Hz, 1H) 6.84 (dd, J=7.33, 2.53Hz, 1H) 6.94-7.00 (m, 2H) 7.43-7.52 (m, 2H). MS (ES) [M+H] calculatedfor C₂₄H₂₈FN₆O₄, 483.50; found 483.30.

Example 36 Synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 37)

Compound 37 was synthesized using an analogous procedure described forExample 39 except that(S)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine was used.¹H NMR (400 MHz, CHLOROFORM-d) δ 1.43-1.55 (m, 1H) 1.66 (m, 1H) 2.55 (s,3H) 2.83-2.95 (m, 2H) 3.11-3.44 (m, 1H) 3.17-3.24 (m, 1H) 3.27-3.33 (m,1H) 3.48-3.56 (m, 1H) 3.65 (s, 3H) 3.89-4.01 (m, 2H) 4.68 (ddd, J=10.23,3.03, 2.91 Hz, 1H) 6.53 (dd, J=8.34, 2.53 Hz, 1H) 6.81 (dd, J=7.33, 2.53Hz, 1H) 6.90 (dt, J=9.28, 2.68 Hz, 1H) 6.96 (td, J=8.40, 2.65 Hz, 1H)7.38-7.43 (m, 1H) 7.44-7.51 (m, 1H). MS (ES) [M+H]⁺calculated forC₂₄H₂₈FN₆O₄, 483.21; found 483.00.

Example 37(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-3,4-dihydroxybutyl oxime (Compound 38)

Compound 38 was synthesized using an analogous procedure described forExample 39 except that(R)—O-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)hydroxylamine was used.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.74-1.93 (m, 1H) 2.13-2.16 (m, 1H)2.66 (s, 3 H) 3.00-3.11 (m, 1H) 3.14-3.24 (m, 1H) 3.32 (d, J=3.03 Hz,1H) 3.50 (ddd, J=11.18, 7.01, 4.55 Hz, 1H) 3.65 (ddd, J=10.74, 6.95,3.54 Hz, 1H) 3.90 (s, 3H) 4.13-4.28 (m, 2H) 4.88 (dd, J=10.61, 4.04 Hz,1H) 5.11 (s, 2H, OH) 5.72 (s, 1H, NH) 6.74 (d, J=8.84 Hz, 1H) 7.00 (d,J=7.83 Hz, 1H) 7.10-7.22 (m, 2H) 7.61-7.70 (m, 2H). MS (ES) [M+H]calculated for C₂₄H₂₈FN₆O₄, 483.21; found 483.30.

Example-38(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)amino)butane-1,2-diol(Compound 39)

Compound 39 was synthesized using an analogous procedure described forExample 39 except that (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanamine(20, Example 2-F) was used. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.55-1.68 (m, 2H) 2.57 (s, 3H) 2.66-2.78 (m, 2H) 3.16 (dd, J=16.17, 3.54Hz, 1H) 3.25 (ddd, J=14.08, 4.29, 4.11 Hz, 1H) 3.41-3.49 (m, 1 H)3.52-3.59 (m, 1H) 3.65-3.78 (m, 1H) 3.88 (s, 3H) 4.83 (dd, J=12.63, 3.03Hz, 1H) 5.30 (br. s., 2H, OH) 6.70 (d, J=8.34 Hz, 1H) 7.01 (d, J=7.33Hz, 1H) 7.10 (dd, J=9.47, 2.65 Hz, 1 H) 7.17 (td, J=8.27, 2.65 Hz, 1H)7.62 (t, J=7.83 Hz, 1H) 7.80 (dd, J=8.59, 5.81 Hz, 1H). MS (ES) [M+H]calculated for C₂₄H₂₈FN₆O₃, 467.21; found 467.30.

Example 39 Synthesis of(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-1,4-dioxan-2-yl)methyl oxime (Compound 40)

Thiolactam (31I (Example 31), 0.087 g, 0.0272 mmol),(R)—O-((1,4-dioxan-2-yl)methyl)hydroxylamine (2M (Example 2-E), 0.145 g,1.09 mmol), and mercury (II) acetate (0.173 g, 0.045 mmol) weredissolved in 3.5 mL of dry toluene and heated in 100° C. oil bath for 1h. The reaction was done as judged by LC/MS. The crude mixture wasfiltered through Celite, rinsed with methanol and then concentrated andpurified on preparatory LC/MS (25-55% CH₃CN in H₂O) to afford(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-1,4-dioxan-2-yl)methyl oxime (39A, 0.0405 g, 36.7% yield). ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 2.90 (s, 3H) 3.04 (dd, J=17.05, 8.97 Hz,2H) 3.28 (dd, J=17.56, 4.17 Hz, 1H) 3.43 (dd, J=11.62, 9.85 Hz, 1H)3.58-3.68 (m, 1H) 3.70-3.76 (m, 2H) 3.77-3.88 (m, 2H) 3.93-4.00 (m, 1H)4.01-4.08 (m, 1H) 4.09-4.18 (m, 1H) 5.01 (d, J=5.05 Hz, 1H) 5.78 (s, 1H)7.11 (td, J=8.21, 2.53 Hz, 1H) 7.37 (dd, J=7.96, 2.65 Hz, 1H) 7.41 (dd,J=8.84, 5.81 Hz, 1H). ESI-MS: m/z 468.1 (M+H)⁺.

39A was reacted with2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (39B)according to a procedure analogous to Example 31, the step of 31H to31J, to afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((R)-1,4-dioxan-2-yl)methyl oxime (40, 37.3% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.55 (s, 3H) 2.85 (dd, J=16.17, 7.07 Hz, 1H) 3.10 (dd,J=16.29, 5.18 Hz, 1H) 3.24-3.35 (m, 1H) 3.45 (dd, J=10.99, 2.65 Hz, 1H)3.50-3.59 (m, 1H) 3.59-3.74 (m, 2H) 3.76-3.84 (m, 3H) 3.86 (s, 3H)3.89-3.96 (m, 1H) 5.10 (m, 1H) 6.54 (br. s., 1H) 6.85 (d, J=8.34 Hz, 1H)7.19 (d, J=7.07 Hz, 1H) 7.23-7.31 (m, 2H) 7.45 (dd, J=8.46, 5.94 Hz, 1H)7.78-7.92 (m, 1H). ESI-MS: m/z 495.3 (M+H)⁺.

Example 40 Preparation of(7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-morpholin-2-ylmethyl oxime and isomers (Compounds 41-43)

40A was prepared by a procedure analogous to that disclosed in Example39 except tert-butyl 2-(aminooxymethyl)morpholine-4-carboxylate wasused. The final Boc-deprotection was effected by treatment of 40A (6 mg,0.01 mmol) with 4N HCl in dioxane (0.7 mL). The reaction was dried invacuo to afford(7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-morpholin-2-ylmethyl oxime as a tan oil (41, quantitative yield). ¹HNMR (400 MHz, MeOD) δ ppm 2.84 (s, 3H) 3.00-3.10 (m, 1H) 3.11-3.21 (m,1H) 3.34-3.50 (m, 2H) 3.53-3.77 (m, 2H) 3.81-3.92 (m, 1H) 4.06 (s, 3H)4.09-4.13 (m, 2H) 4.13-4.21 (m, 2H) 4.95-4.99 (m, 1H) 7.11-7.18 (m, 1H)7.23-7.29 (m, 1H) 7.29-7.38 (m, 2H) 7.67-7.76 (m, 1H) 8.04-8.12 (m, 1H).[M+H]⁺ calc'd for C₂₅H₂₈FN₇O₃, 494; found, 494. SFC separation of 41yields the two enantiomers.

(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-morpholin-2-ylmethyl oxime (42). ¹H NMR (400 MHz, MeOD) δ ppm 2.82(s, 3H) 2.95-3.28 (m, 4H) 3.33-3.45 (m, 2H) 3.83 (td, J=12.57, 2.40 Hz,1H) 3.92 (s, 3H) 4.02-4.21 (m, 4H) 5.07 (dd, J=8.84, 4.29 Hz, 1H) 6.81(d, J=8.34 Hz, 1H) 7.13 (d, J=7.33 Hz, 1H) 7.17-7.29 (m, 2H) 7.63 (dd,J=8.59, 5.56 Hz, 1H) 7.78 (t, J=7.83 Hz, 1H). [M+H] calc'd forC₂₅H₂₈FN₇O₃, 494; found, 494.

(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-morpholin-2-ylmethyl oxime (43). ¹H NMR (400 MHz, MeOD) δ ppm 2.82(s, 3H) 2.95-3.28 (m, 4H) 3.33-3.45 (m, 2H) 3.83 (td, J=12.57, 2.40 Hz,1H) 3.92 (s, 3H) 4.02-4.21 (m, 4H) 5.07 (dd, J=8.84, 4.29 Hz, 1H) 6.81(d, J=8.34 Hz, 1H) 7.13 (d, J=7.33 Hz, 1H) 7.17-7.29 (m, 2H) 7.63 (dd,J=8.59, 5.56 Hz, 1H) 7.78 (t, J=7.83 Hz, 1H). [M+H] calc'd forC₂₅H₂₈FN₇O₃, 494; found, 494.

Example 41 Synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—O₂R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methyl oxime (44) andits analog (Compound 44) and stereoisomers (Compounds 45, 46, 47, and48)

Reaction of 31I and O-(((3 aR, 4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine(2Y) according to a procedure analogous to Example 39 yielded a racemicmixture of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((3 aR, 4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyloxime. Prep LC/MS (40-85% NH₄OAc—H₂O—AcCN) separation yielded thediastereomers 41A and 41B.

The diastereomers, 41A and 41B, were each separately coupled to2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineaccording also according to the procedure described in Example 39.Deprotection and prep LC/MS (40-85% NH₄OAc—H₂O—AcCN) separation of eachof the reaction mixtures yielded a hydroxyl analog and twostereoisomers.

(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3S,4R)-3,4,5-trihydroxytetrahydrofuran-2-yl)methyl oxime (44). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 2.35 (s, 3H) 2.67-2.72 (m, 1H)2.78-2.90 (m, 1H) 3.29 (dt, J=11.94, 2.87 Hz, 1H) 3.39-3.48 (m, 1H) 3.59(s, 3H) 3.65-3.77 (m, 1H) 3.82-3.90 (m, 1H) 3.91-4.01 (m, 1H) 4.57-4.69(m, 1H) 4.83-4.97 (m, 1H) 6.37-6.50 (m, 1H) 6.75 (d, J=7.33 Hz, 1H)6.79-6.91 (m, 2H) 7.32-7.44 (m, 2 H). MS (ES) [M+H] calculated forC₂₅H₂₈FN₆O₆, 527.20; found 527.20.

(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3S,4R,5R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyloxime (45). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44 (s, 3H) 2.72-2.84(m, 1H) 2.88-2.97 (m, 1H) 3.05 (s, 3H) 3.68 (s, 3H) 3.70 (d, J=2.27 Hz,1H) 3.81-3.94 (m, 2H) 3.95-4.03 (m, 2H) 4.56 (s, 1H) 4.69 (dd, J=9.98,3.16 Hz, 1H) 6.53 (d, J=8.34 Hz, 1H) 6.82 (d, J=7.33 Hz, 1H) 6.88-7.00(m, 2H) 7.39-7.52 (m, 2H). MS (ES) [M+H] calculated for C₂₆H₃₀FN₆O₆,541.21; found 541.20.

(R,Z)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyloxime (46). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 3H) 1.27 (s,3H) 2.46 (s, 3H) 2.79-2.88 (m, 1H) 2.92-3.01 (m, 1H) 3.08 (s, 3H) 3.69(s, 3H) 3.78-3.91 (m, 2H) 4.32 (t, J=6.44 Hz, 1H) 4.37 (d, J=5.81 Hz,1H) 4.57 (d, J=6.06 Hz, 1H) 4.72 (dd, J=10.74, 3.66 Hz, 1H) 4.75 (s, 1H)6.56 (d, J=9.85 Hz, 1H) 6.84 (d, J=6.32 Hz, 1H) 6.90-7.04 (m, 2H)7.44-7.54 (m, 2H). MS (ES) [M+H] calculated for C₂₉H₃₄FN₆O₆, 581.24;found 581.30.

(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyloxime (47). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3H) 2.81-2.91(m, 1H) 2.96-3.04 (m, 1H) 3.12 (s, 3H) 3.74 (s, 3H) 3.77 (d, J=4.80 Hz,1H) 3.92-4.00 (m, 2H) 4.01-4.07 (m, 2H) 4.63 (s, 1H) 4.74 (dd, J=10.36,4.04 Hz, 1H) 6.59 (d, J=8.08 Hz, 1H) 6.88 (d, J=7.07 Hz, 1H) 6.94-7.07(m, 2H) 7.52 (t, J=7.83 Hz, 2H). MS (ES) [M+H] calculated forC₂₆H₃₀FN₆O₆, 541.21; found 541.20.

-   (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-((3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl    oxime (48) ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (s, 3H) 1.20    (s, 3H) 2.40 (s, 3H) 2.72-2.81 (m, 1H) 2.86-2.94 (m, 1H) 3.02 (s,    3H) 3.63 (s, 3H) 3.64-3.79 (m, 3H) 4.26 (t, J=6.69 Hz, 1H) 4.51 (d,    J=4.55 Hz, 1H) 4.62-4.70 (m, 2H) 6.50 (d, J=8.59 Hz, 1H) 6.79 (d,    J=7.33 Hz, 1H) 6.85-6.95 (m, 2H) 7.39-7.47 (m, 2H). MS (ES) [M+H]    calculated for C₂₉H₃₄FN₆O₆, 581.24; found 581.30.

Example 42 General Procedure for Suzuki Coupling

Into a 5 mL microwave vial was charged(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(61-p-one(31H (Example 31), 100 mg, 0.28 mmol, 1 eq), boronic acid 42A (4 eq),and Pd(dppf)Cl₂ CH₂Cl₂ (93 mg, 0.11 mmol, 0.4 eq). The compounds weredissolved in a mixture of DMA (3 mL) and 2M K₂CO₃ (1 mL, 8 eq) and thevial was sealed. The reaction mixture was heated to 120° C. for 10 minin a microwave reactor. After cooling to RT, the reaction mixture wasdiluted with DCM and washed with H₂O (X₃) and saturated brine, thendried over anhydrous sodium sulfate, filtered, and evaporated underreduced pressure to give crude product. The crude material was purifiedvia preparative HPLC to yield the pure TFA salt of the product 42B as anoff-white solid.

Example 43 Preparation of (R)-2-amino-7-(5-fluoro-3′-((4-(trifluo romethoxy)phenoxy)methyl)biphenyl-2-yl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one(43A)

Compound 43A was prepared by the method outlined in Example 42 using3-((4-(trifluoromethoxy)phenoxy)methyl)phenylboronic acid. ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 2.79 (s, 3H) 2.86-2.93 (m, 1H) 3.08 (dd,J=16.80, 11.75 Hz, 1H) 4.83 (dd, J=11.49, 4.42 Hz, 1H) 5.07 (s, 2H)6.91-6.97 (m, 3H) 6.98-7.05 (m, 2H) 7.17-7.24 (m, 2H) 7.45-7.48 (m, 1H)7.51-7.62 (m, 2H) 7.66-7.75 (m, 1H). ESI-MS: m/z 539 (MH⁺).

Example 44 Preparation of(R)-2-amino-7-(5-fluoro-2′-((3-(1,1-dioxidoisothiazolidin-2-yl)methyl)biphenyl-2-yl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (41A)

The title compound 44A was prepared by the method outlined in Example 42using 3-(1,1-dioxidoisothiazolidin-2-yl)phenylboronic acid. ¹H NMR (400MHz, MeOD) δ ppm 2.50 (quin, J=6.88 Hz, 2H) 2.80 (s, 3H) 3.00 (dd,J=17.05, 4.17 Hz, 1H) 3.23-3.29 (m, 1H) 3.43 (t, J=7.45 Hz, 2H) 3.80 (t,J=6.44 Hz, 2H) 4.90-4.93 (m, 1H) 7.06 (dd, J=9.22, 2.40 Hz, 1H) 7.12 (d,J=7.58 Hz, 1H) 7.19-7.28 (m, 3H) 7.45 (t, J=7.83 Hz, 1H) 7.69 (dd,J=8.84, 5.56 Hz, 1H). ESI-MS: m/z 468 (MH⁺).

Example 45(R,Z)-2-Amino-7-(3′-(cyclopropylsulfonyl)-5-fluorobiphenyl-2-yl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-2,3-dihydroxypropyl oxime (Compound 49)

Compound 45A was synthesized according to the procedure of Example 39using (S)—O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine3-(cyclopropylsulfonyl)phenylboronic acid was then coupled to 45Aaccording to the Suzuki coupling reaction of Example 42 yielding thetitle compound 49. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.76-0.88 (m,1H) 0.99-1.11 (m, 1H) 2.29-2.38 (m, 1H) 2.45 (s, 3H) 2.60 (dd, J=16.55,3.66 Hz, 1H) 2.81 (dd, J=16.42, 10.86 Hz, 1H) 3.28-3.43 (m, 1H)3.70-3.76 (m, 1H) 3.77-3.85 (m, 1H) 3.85-3.92 (m, 1H) 4.21 (dd, J=10.86,3.28 Hz, 1H) 6.78 (dd, J=9.09, 2.53 Hz, 1H) 6.98 (td, J=8.27, 2.40 Hz,1H) 7.37-7.48 (m, 3H) 7.62 (s, 1H) 7.68 (dt, 1H). MS (ES) [M+H]calculated for C₂₆H₂₉FN₅O₅S, 542.18; found 542.20.

Example 46(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-methoxybutanoicacid (Compound 50)

A. Synthesis of (S)-methyl 4-(aminooxy)-2-methoxybutanoate

To a suspension of NaH (60% in mineral oil, 552 mg, 12.0 mmol) in THF (5mL) was added a solution of (S)-3-hydroxydihydrofuran-2(3H)-one (46a,1.02 g, 10.0 mmol) in THF (5 mL) slowly drop wise at 0° C. under N₂atmosphere. The reaction mixture was stirred for 30 minutes anddimethylsulphate (1.4 mL, 15.0 mmol) was added. The reaction mixture wasstirred at r.t. overnight and the TLC shows completion of the reaction.Cold water (25 mL) was added to the reaction mixture and extracted withethyl acetate. Organic layer washed with brine, dried over anhydrousNa₂SO₄ and filtered. Concentrated to provide (S)-3-hydr oxy dihydrofuran-2(3H)-one (46a) as yellow oil, which was dissolved in MeOH.Catalytic amount of K₂CO₃ (50 mg) was added at 0° C. and the reactionmixture stirred for 1 h. TLC shows completion of the reaction. Coldwater (25 mL) was added to the reaction mixture and extracted with ethylacetate. Organic layer washed with brine, dried over anhydrous Na₂SO₄and filtered. Concentrated to provide (S)-methyl4-hydroxy-2-methoxybutanoate (46b, 1.5 g, 99%) as yellow oil. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 2.07-2.28 (m, 1H) 2.36-2.58 (m, 1H) 3.36(s, 3H) 3.49 (s, 3H) 3.85-4.07 (m, 1H) 4.29-4.42 (m, 2H).

To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g,10.0 mmol) in CH₂Cl₂ (25.0 mL) was added 2-hydroxyisoindoline-1,3-dione(1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). Theresultant mixture was cooled to 0° C. and diisopropylazodicarboxylate(2.95 ml, 15.0 mmol) was slowly added drop wise under N₂ atmosphere. Thereaction mixture was stirred at ambient temperature for 48 h. To thereaction mixture, H₂O (100 mL) was added and extracted with CH₂Cl₂. Theorganic layers washed with brine. Dried over anhydrous Na₂SO₄, filteredand concentrated to provide yellow oil, which was purified by flashchromatography (50% EtOAc-hexane) to afford (S)-methyl4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) aslight yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H)2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz,1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).

To a solution of (S)-methyl4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (1.2 g, 4.0 mmol) inCH₂Cl₂ (5.0 ml) was added hydrazine hydrate (0.98 mL, 10.0 mmol) wasadded drop wise at 0° C. The reaction mixture was stirred at ambienttemperature over night. The resultant solid was filtered off and thefiltrate concentrated under reduced pressure to provide a yellow oil,which was purified by flash chromatography (70% EtOAc-hexane) to afford(S)-methyl 4-(aminooxy)-2-methoxybutanoate (46c, 0.552 g, 84%) as a paleyellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.75-2.23 (m, 2H) 3.40(s, 3H) 3.46 (s, 3H) 3.65-3.86 (m, 2H) 4.96 (dt, J=12.57, 6.22 Hz, 1H).

B. Preparation of Compound 50

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(311, 146 mg, 0.4 mmol), (S)-methyl 4-(aminooxy)-2-methoxybutanoate(46c, 260 mg, 1.6 mmol), Hg(OAc)₂ (257 mg, 0.8 mmol) and toluene (2 mL)was heated at 100° C. for 2 h. Cooled to rt, filtered through celite andpurified to afford (S)-methyl4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-methoxybutanoate(23 mg, 12%) as off white solid. MS (ES) [M+H] calculated forC₂₀H₂₄BrFN₅O₄, 496.09; found 496.20.

A mixture of the resultant compound (23 mg, 0.05 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (74.5 mg,0.25 mmol), Pd(dppf)₂Cl₂ (4.0 mg, 0.005 mmol), 2N aq Na₂CO₃ (0.25 mL,0.5 mmol) and DMA (2 mL) was degassed with N₂ and heated at 85° C. for 4h. During the reaction, the methyl ester saponified in situ. Cooled tort, filtered trough celite and purified to afford(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-methoxybutanoicacid (4.6 mg, 20%) as off white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.91-2.03 (m, 1H) 2.10-2.24 (m, 1H) 2.74 (s, 3H) 2.84-2.98 (m, 1H)3.00-3.10 (m, 1H) 3.31 (br. s., 3H) 3.75-3.79 (m, 1H) 3.81 (s, 3H)4.02-4.16 (m, 2H) 4.82 (ddd, J=10.23, 2.91, 2.78 Hz, 1H) 6.69 (dd,J=8.34, 2.02 Hz, 1H) 6.95 (dd, J=7.20, 1.89 Hz, 1H) 7.06 (ddd, J=9.16,2.46, 2.27 Hz, 1H) 7.09-7.16 (m, 1H) 7.60 (dddd, J=15.73, 8.15, 7.96,2.27 Hz, 2 H). MS (ES) [M+H] calculated for C₂₅H₂₈FN₆O₅, 511.20; found511.40.

Example 47(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3S, 4S)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime (Compound51)

To a solution of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3S,4R)-3,4-dihydroxy-5-methoxytetrahydrofuran-2-yl)methyl oxime(10.5 mg, 0.02 mmol) in CH₂Cl₂ (1 mL) was added Et₃SiH (16 μL, 0.05mmol) and BF₃.Et₂O (8.0 μL, 0.05 mmol) at 0° C. under N₂ atmosphere. Thereaction mixture was stirred overnight at r.t. and poured on crushedice. The resultant slurry was extracted with CH₂Cl₂ and washed withbrine. Work-up and purification by Preparative LCMS afforded the titlecompound (3.0 mg, 30%) as light brown solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.50 (s, 3H) 2.77 (dd, J=16.04, 6.95 Hz, 1H) 3.00(dd, J=16.04, 5.18 Hz, 1H) 3.15-3.26 (m, 2H) 3.35-3.42 (m, 2H) 3.83 (s,3H) 3.85-3.94 (m, 2H) 4.38-4.41 (m, 1H) 4.93-5.13 (m, 1H) 6.82 (d,J=9.09 Hz, 1H) 7.16 (d, J=7.07 Hz, 1H) 7.21-7.30 (m, 2 H) 7.45 (dd,J=8.46, 5.94 Hz, 1H) 7.86 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H]calculated for C₂₅H₂₈FN₆O₅, 511.51; found 511.20.

Example 48 (2S,4R)-tert-butyl2-(aminooxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate

To a solution of (2S,4R)-tert-butyl4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(2.0 g, 6.0 mmol) in CH₂Cl₂ (15.0 mL) was added2-hydroxyisoindoline-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine(2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. anddiisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added dropwise under N₂ atmosphere. The reaction mixture was stirred at ambienttemperature for 48 h. To the reaction mixture, H₂O (100 mL) was addedand extracted with CH₂Cl₂. The organic layers washed with brine. Driedover anhydrous Na₂SO₄, filtered and concentrated to provide yellow oil,which was purified by flash chromatography (50% EtOAc-hexane) to yield(2S,4R)-tert-butyl4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylateas light yellow oil.

The resultant oily compound was dissolved in CH₂Cl₂ (250 ml) and cooledto 0° C. Hydrazine hydrate (1.2 mL, 12.0 mmol) was added dropwise. Thereaction mixture was stirred at ambient temperature over night. Theresultant solid was filtered off and the filtrate concentrated underreduced pressure to provide a yellow oil, which was purified by flashchromatography (70% EtOAc-hexane) to afford 1.2 g (60%, over two steps)of (2S,4R)-tert-butyl2-(aminooxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylateas a pale yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.24 (s, 3H)0.26 (s, 3H) 0.87 (s, 9H) 1.26 (s, 9H) 1.67-1.76 (m, 1H) 1.81-1.94 (m,1H) 3.18 (dd, J=12.25, 4.93 Hz, 1H) 3.22-3.31 (m, 1H) 3.70-3.81 (m, 1H)3.88-3.96 (m, 1H) 3.98-4.09 (m, 1H) 4.12-4.21 (m, 1H). MS (ES) [M+H]calculated for C₁₆H₃₅N₂O₄Si, 347.23; found 347.22.

Example 49(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2S,4R)-4-hydroxypyrrolidin-2-yl)methyl oxime (Compound 52)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(183 mg, 0.5 mmol), (2S,4R)-tert-butyl2-(aminooxymethyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate(692 mg, 2.0 mmol), Hg(OAc)₂ (320 mg, 1.0 mmol) and toluene (2 mL) washeated at 100° C. for 2 h. Cooled to r.t., filtered through celite andpurified to afford (2S,4R)-tert-butyl24(Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5-(6H)-ylidene)aminooxy)methyl)-4-(tert-butyldimethylsilyloxy)pyrrolidine-1-carboxylate(200 mg, 50%) as off white solid. MS (ES) [M+H] calculated forC₃₀H₄₅BrFN₆O₄Si, 679.24; found 679.20.

A mixture of the resultant compound (200 mg, 0.3 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (447 mg, 1.5mmol), Pd(dppf)₂Cl₂ (25 mg, 0.03 mmol), 2N aq Na₂CO₃ (1.5 mL, 3.0 mmol)and DMA (2 mL) was degassed with N₂ and heated at 85° C. for 4 h. Cooledto rt, filtered trough celite and purified to afford (2S,4R)-tert-butyl24(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-4-hydroxypyrrolidine-1-carboxylate(94 mg, 53%) as a viscous oil. MS (ES) [M+H] calculated for C₃₀H₃₇FN₇O₅,594.28; found 594.30. The resultant oily compound was dissolved indioxane (1.0 ml) and cooled to 0° C. 4N HCl in dioxane (0.1 mL, 0.375mmol) was added and the reaction mixture was stirred at ambienttemperature for 2 h. The resultant solid was filtered off and dried toafford Compound 52 as an HCl salt (56 mg, 76%) as white solid. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.64 (ddd, J=13.64, 8.08, 5.56 Hz, 1H)1.88 (dd, J=13.64, 7.07 Hz, 1H) 2.65 (s, 3H) 2.90 (d, J=11.62 Hz, 1H)3.00-3.09 (m, 2H) 3.13-3.27 (m, 1H) 3.68-3.82 (m, 1H) 3.84-3.94 (m, 4 H)3.95-4.02 (m, 1H) 4.40 (t, J=4.67 Hz, 1H) 4.87 (dd, J=10.48, 3.92 Hz,1H) 5.18 (s, 2H) 5.72 (s, 1H) 6.73 (d, J=8.34 Hz, 1H) 7.00 (d, J=7.07Hz, 1H) 7.07-7.24 (m, 2H) 7.57-7.77 (m, 2H). MS (ES) [M+H] calculatedfor C₂₅H₂₉FN₇O₃, 494.22; found 494.20.

Example 50(3R,5S)-1-acetyl-5-4(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)pyrrolidin-3-ylacetate (Compound 53)

To a solution of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2S,4R)-4-hydroxypyrrolidin-2-yl)methyl oxime (20 mg, 0.05 mmol) inCH₂Cl₂ (1 mL) containing catalytic amount of DMAP was added Et₃N (20.86μL, 0.15 mmol) and acetyl chloride (10.0 μL, 0.1 mmol) at 0° C. under N₂atmosphere. The reaction mixture was stirred at r.t. for 2 h. Quenchedwith sat NH₄Cl solution and extracted with CH₂Cl₂. The combined organiclayers washed with brine, dried over anhydrous Na₂SO₄. The resultantresidue was purified by preparative LCMS to afford the title compound (5mg, 25%) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.00 (s,3H) 2.04 (s, 3H) 2.09-2.23 (m, 1H) 2.29-2.41 (m, 1H) 2.64 (s, 3H)2.95-3.11 (m, 1H) 3.15-3.29 (m, 1H), 3.66 (dd, J=11.37, 5.56 Hz, 1H)3.90 (s, 3H) 4.04 (dd, J=11.87, 5.31 Hz, 1 H) 4.13-4.30 (m, 1H)4.32-4.49 (m, 1H) 4.77-4.95 (m, 1H), 5.06-5.16 (m, 1H) 5.20-5.32 (m, 1H)6.74 (d, J=8.34 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.10-7.22 (m, 2H)7.57-7.74 (m, 2H). MS (ES) [M+H] calculated for C₂₉H₃₃FN₇O₅, 578.60;found 578.30.

Example 51 (2S,4R)-1-tert-butyl 2-methyl4-(aminooxy)pyrrolidine-1,2-dicarboxylate

To a solution of (2S,4R)-1-tert-butyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (4.9 g, 20.0 mmol) in CH₂Cl₂(50.0 mL) was added 2-hydroxyisoindoline-1,3-dione (3.26 g, 20.0 mmol)and triphenylphosphine (7.86 g, 30.0 mmol). The resultant mixture wascooled to 0° C. and diisopropylazodicarboxylate (5.90 ml, 30.0 mmol) wasslowly added drop wise under N₂ atmosphere. The reaction mixture wasstirred at ambient temperature for 48 h. Work-up and purification asdescribed in Example 2A, Step 1 afforded (2S,4R)-1-tert-butyl 2-methyl4-(1,3-dioxoisoindolin-2-yloxy)pyrrolidine-1,2-dicarboxylate as aviscous oil. The resultant oily compound was dissolved in CH₂Cl₂ (100ml) and cooled to 0° C. Hydrazine hydrate (4.0 mL, 40.0 mmol) was addeddrop wise. The reaction mixture was stirred at ambient temperature overnight. Work-up and purification as described in Example 2A, Step 2afforded (2.8 g, 53%, over two steps) of (2S,4R)-1-tert-butyl 2-methyl4-(aminooxy)pyrrolidine-1,2-dicarboxylate as a pale yellow oil. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 2.13-2.29 (m, 1H) 2.34-2.48(m, 1H) 3.48-3.68 (m, 2H) 3.72 (s, 3H) 4.23-4.30 (m, 1H) 4.30-4.49 (m,1H). MS (ES) [M+H] calculated for C₁₁H₂₁N₂O₅, 261.14; found 261.22.

Example 52 (2S,4R)-methyl4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-2-carboxylate(Compound 54)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(150 mg, 0.4 mmol), (2S,4R)-1-tert-butyl 2-methyl4-(aminooxy)pyrrolidine-1,2-dicarboxylate (416 mg, 1.6 mmol), Hg(OAc)₂(256 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h.Cooled to rt, filtered through celite and purified to afford(2S,4R)-1-tert-butyl 2-methyl4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-1,2-dicarboxylate(172 mg, 570%) as off white solid. MS (ES) [M+H] calculated forC₂₅H_(3i)BrFN₆O₅, 593.14; found 593.10.

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(150 mg, 0.4 mmol), (2S,4R)-1-tert-butyl 2-methyl4-(aminooxy)pyrrolidine-1,2-dicarboxylate (416 mg, 1.6 mmol), Hg(OAc)₂(256 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h.Cooled to rt, filtered through celite and purified to afford(2S,4R)-1-tert-butyl 2-methyl4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-1,2-dicarboxylate(172 mg, 570%) as off white solid. MS (ES) [M+H] calculated forC₂₅H_(3i)BrFN₆O₅, 593.14; found 593.10.

The resultant oily compound was dissolved in dioxane (1.0 ml) and cooledto 0° C. 4N HCl in dioxane (62.0 μL, 0.25 mmol) was added and thereaction mixture was stirred at ambient temperature for 2 h. Theresultant solid was filtered off and dried to afford Compound 54 as anHCl salt (45.0 mg, 82%) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 2.32-2.46 (m, 2H) 2.53 (s, 3H) 2.87 (dd, J=16.80, 10.74 Hz, 2H) 3.12(d, J=4.04 Hz, 1H) 3.30 (dd, J=12.63, 3.54 Hz, 1H) 3.47 (s, 3H) 3.71 (s,3H) 4.38 (dd, J=9.98, 2.65 Hz, 1H) 4.67 (t, J=3.79 Hz, 1H) 4.73 (dd,J=10.23, 3.66 Hz, 1H) 6.60 (d, J=8.34 Hz, 1H) 6.87 (d, J=7.07 Hz, 1H)6.97 (dd, J=9.22, 2.65 Hz, 1H) 7.03 (td, J=8.46, 2.02 Hz, 1H) 7.46 (dd,J=9.09, 4.80 Hz, 1H) 7.53 (t, J=7.71 Hz, 1H). MS (ES) [M+H] calculatedfor C₂₆H₂₉PN₇O₄, 522.542; found 522.24

Example 53(2S,4R)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-2-carboxylicacid (Compound 55)

The title compound was prepared analogous to the procedure described forExample 52. ¹H NMR (400 MHz, MeOD) δ ppm 2.23-2.36 (m, 1H) 2.39-2.49 (m,1H) 2.69 (s, 3H) 3.14-3.26 (m, 2H) 3.43-3.54 (m, 2H) 3.76 (s, 3H)4.14-4.26 (m, 1H) 4.53 (dd, J=9.09, 3.79 Hz, 1H) 4.60 (d, J=2.27 Hz, 1H)6.82-6.91 (m, 1H) 6.93-7.09 (m, 2H) 7.20-7.32 (m, 1H) 7.44 (dd, J=8.84,5.31 Hz, 1H) 7.68-7.90 (m, 1H). MS (ES) [M+H] calculated forC₂₅H₂₇FN₇O₄, 507.51; found 508.20.

Example 54(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl oxime (Compound 56)

To a solution of (2S,4R)-methyl4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-2-carboxylate (25.0 mg, 0.04 mmol) in dry ether (1mL) was added LiAlH₄ (0.1 mL, 0.01 mmol, 1M solution in ether) at 0° C.under N₂ atmosphere. Stirred for 1 h and quenched with 1N NaOH (0.1 mL)solution. Anhydrous MgSO₄ was added and filtered through celite. Thefiltrate was concentrated under reduced pressure and purified bypreparative LCMS to afford the title compound (6.0 mg, 32%) as a whitesolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-1.95 (m, 2H) 2.47 (s,3H) 2.58 (d, J=3.03 Hz, 1H) 2.71 (d, J=3.28 Hz, 1H) 2.94-3.00 (m, 2H)3.13-3.19 (m, 1H) 3.22-3.39 (m, 2H) 3.43 (dd, J=11.12, 6.32 Hz, 1H) 3.58(s, 3H) 4.65-4.73 (m, 1H) 6.47 (dd, J=8.46, 2.91 Hz, 1H) 6.76 (dd,J=7.20, 2.65 Hz, 1H) 6.84 (ddd, J=9.73, 2.78, 2.65 Hz, 1H) 6.87-6.93 (m,1H) 7.29-7.36 (m, 1H) 7.41 (t, J=7.83 Hz, 1H). MS (ES) [M+H] calculatedfor C₂₅H₂₉FN₇O₃, 494.53; found 494.20.

Example 55 (3aR,4R, 6aS)-tert-butyl4-(aminooxymethyl)-2,2-dimethyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate

To a solution of (S)-1-tert-butyl 2-methyl 1H-pyrrole-1, 2(2H,5H)-dicarboxylate (1.0 g, 4.5 mmol) in dioxane —H₂O (4:1) was added NMO(580 mg, 4.95 mmol) and OsO₄ 114 mg, 0.45 mmol, 2.5 wt % in H₂O) and thereaction mixture was stirred for 24 h at r.t. Quenched with 10% aqueousNa₂S₂O₃ solution and extracted with ethyl acetate. The combined organiclayers washed with brine and dried over anhydrous Na₂SO₄. The resultantresidue was dissolved in acetone (5 mL), added catalytic amount of PPTSand dimethoxy propane (1.5 mL). The reaction mixture was stirred overnight at r.t. and diluted with ethyl acetate, washed with saturatedNaHCO₃ and brine. Dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was dissolved in ether (5.0 mL) and LiAlH₄(3.0 mL, 3.0 mmol, 1M solution in ether) was added at 0° C. under N₂atmosphere. Stirred for 1 h and quenched with 1N NaOH (0.1 mL) solution.Anhydrous Mg50₄ was added and filtered through celite. The filtrate wasconcentrated under reduced pressure and purified by flash chromatography(5% MeOH—CH₂Cl₂) to afford (3aR,4R, 6aS)-tert-butyl4-(hydroxymethyl)-2,2-dimethyldihydro-3aH-[1, 3]dioxolo[4,5-c]pyrrole-5(4H)-carboxylate (550 mg, 45%, over 3 steps). ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 6H) 1.47 (s, 9H) 3.33-3.38(m, 1H) 3.50 (dd, J=13.14, 6.06 Hz, 2H) 4.54 (d, J=3.79 Hz, 1H)4.59-4.61 (m, 1H) 4.66-4.73 (m, 2H).

The resultant oily compound (550 mg, 2.0 mmol) was subjected to theMitsunobu coupling followed by phthalimide deprotection analogous to theprocedure described in Example 2 afforded (3aR,4R, 6aS)-tert-butyl4-(aminooxymethyl)-2,2-dimethyldihydro-3aH-[1,3]dioxolo[4,5-c]pyrrole-5(411)-carboxylate (340 mg, 59%) as a viscousoil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 3H) 1.45 (s, 3H) 1.47(s, 9H) 3.26-3.47 (m, 1H) 3.59-3.80 (m, 2H) 4.07-4.38 (m, 1H) 4.51-4.67(m, 1H) 5.41-5.71 (m, 2H). MS (ES) [M+H] calculated for C₁₃H₂₅N₂O₅,289.17; found 289.20.

Example 56(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((2R,3R, 4S)-3,4-dihydroxypyrrolidin-2-yl)methyl oxime (Compound 57)

The title compound was prepared according to the procedure described forexample # using(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(150 mg, 0.4 mmol) and (3aR,4R, 6a5)-tert-butyl4-(aminooxymethyl)-2,2-dimethyldihydro-3aH-[1, 3]dioxolo[4,5-c]pyrrole-5(411)-carboxylate (340 mg, 1.2 mmol). Suzukicoupling followed by deprotection afforded the title compound as a whitesolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.53 (s, 3H) 2.85-2.99 (m,1H) 3.02-3.15 (m, 1H) 3.18-3.25 (m, 1H) 3.26-3.31 (m, 2H) 3.81 (s, 3H)3.83-3.95 (m, 1H) 3.97-4.04 (m, 1H) 4.10 (brs, 1H) 4.20-4.29 (m, 1H)4.37 (d, J=4.80 Hz, 1H) 4.60 (brs, 1H) 4.81 (dd, J=9.47, 3.41 Hz, 1H)6.68 (d, J=8.34 Hz, 1H) 6.95 (d, J=7.07 Hz, 2H) 7.01-7.14 (m, 1H)7.48-7.57 (m, 1H) 7.61 (t, J=7.71 Hz, 1H). MS (ES) [M+H] calculated forC₂₅H₂₉FN₇O₄, 510.53; found 510.40.

Example 57 (1R,2S)-4-(aminooxy)cyclopentane-1,2-diol

To a solution of cyclopent-3-enol (840 mg, 10.0 mmol) in CH₂Cl₂ (25.0mL) was added 2-hydroxyisoindoline-1,3-dione (1.96 g, 12.0 mmol) andtriphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooledto 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowlyadded drop wise under N₂ atmosphere. The reaction mixture was stirred atambient temperature for 48 h. To the reaction mixture, H₂O (100 mL) wasadded and extracted with CH₂Cl₂. The organic layers washed with brine.Dried over anhydrous Na₂SO₄, filtered and concentrated to provide yellowoil, which was purified by flash chromatography (50% EtOAc-hexane) toyield 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (740 mg, 32%) aslight yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57-2.87 (m, 4H)5.12 (t, J=6.19 Hz, 1H) 5.75 (s, 2H) 7.74 (dd, J=5.68, 3.16 Hz, 2H)7.79-7.87 (m, 2H). MS (ES) [M+H] calculated for C₁₃H₁₂NO₃, 230.07; found230.20.

To a solution of 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (736 mg,3.2 mmol) in dioxane —H₂O (5.0 mL, 4:1) was added NMO (421 mg, 3.60mmol) and OsO₄ (1.0 mL mg, 0.32 mmol, 2.5 wt % in H₂O) and the reactionmixture was stirred for 24 h at rt. Quenched with 10% aqueous Na₂S₂O₃solution and extracted with ethyl acetate. The combined organic layerswashed with brine and dried over anhydrous Na₂SO₄. Filtered andconcentrated to provide yellow oil, which was purified by flashchromatography (80% EtOAc-hexane) to yield2-((3R,45)-3,4-dihydroxycyclopentyloxy)isoindoline-1,3-dione (650 mg,77%) as light yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.94-2.12(m, 2H) 2.14-2.35 (m, 2H) 4.22-4.88 (m, 2H) 4.75-5.11 (m, 1H) 7.67-7.78(m, 2H) 7.79-7.86 (m, 2H). MS (ES) [M+H] calculated for C₁₃H₁₄NO₅,264.08; found 264.20.

The resultant oily compound (650 mg, 2.47 mmol) was dissolved in CH₂Cl₂(5 ml) and cooled to 0° C. Hydrazine hydrate (0.3 mL, 6.17 mmol) wasadded dropwise. The reaction mixture was stirred at ambient temperatureover night. The resultant solid was filtered off and the filtrateconcentrated under reduced pressure to afford (248 mg, 71%) of(1R,2S)-4-(aminooxy)cyclopentane-1,2-diol as a pale yellow oil. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.67-1.87 (m, 4H) 3.86-3.96 (m, 2H)4.00-4.21 (m, 1H). MS (ES) [M+H] calculated for C₆H₁₂NO₃, 134.07; found134.21.

Example 58 (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(3R,4S)-3,4-dihydroxycyclopentyl oxime (Compound 58)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(146 mg, 0.4 mmol), (1R,2S)-4-(aminooxy)cyclopentane-1,2-diol (212 mg,1.6 mmol), Hg(OAc)₂ (256 mg, 0.8 mmol) and toluene (2 mL) was heated at100° C. for 2 h. Cooled to rt, filtered through celite and purified toafford(7R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(3R,4S)-3,4-dihydroxycyclopentyl oxime (78 mg, 43%) as off whitesolid. MS (ES) [M+H] calculated for C₁₉H₂₂BrFN₅O₃, 466.08; found 467.30.

A mixture of the resultant compound (75 mg, 0.16 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (238 mg, 0.8mmol), Pd(dppf)₂Cl₂ (13 mg, 0.016 mmol), 2N aq Na₂CO₃ (0.4 mL, 0.8 mmol)and DMA (2 mL) was degassed with N₂ and heated at 85° C. for 4 h. Cooledto r.t., filtered trough celite and purified to afford (7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(3R, 4S)-3,4-dihydroxycyclopentyl oxime (8.4 mg, 12%) as white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.75-2.03 (m, 4H) 2.51 (s, 3H)2.71-2.89 (m, 1H) 2.95-3.10 (m, 1H) 3.86 (s, 3H) 4.36 (d, J=3.28 Hz, 2H)4.49-4.63 (m, 1H) 4.94 (m, 1H) 6.85 (d, J=7.83 Hz, 1H) 7.19 (d, J=7.33Hz, 1H) 7.22-7.32 (m, 2H) 7.42-7.54 (m, 1H) 7.84 (t, J=7.58 Hz, 1 H). MS(ES) [M+H] calculated for C₂₅H₂₈FN₆O₄, 495.52; found 495.40.

Example 59 (1R,2S)-4-(aminooxymethyl)cyclopentane-1,2-diol

The title compound was prepared analogous to the procedure described inExample 57. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-1.38 (m, 2H)1.50-1.64 (m, 2H) 1.69-1.84 (m, 1H) 3.86-3.96 (m, 2H) 4.11 (dd, J=7.33,1.52 Hz, 2H). MS (ES) [M+H] calculated for C₆H₁₄NO₃, 148.09; found148.07.

Example 60(7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((3R,4S)-3,4-dihydroxycyclopentyl)methyl oxime (Compound 59)

The title compound was prepared analogous to the procedure described inExample 58. ¹H NMR (400 MHz, MeOD) δ 1.54-1.69 (m, 2H), 1.73-1.88 (m,2H), 2.61 (s, 3H), 2.64-2.75 (m, 1H), 2.90-3.03 (m, 1H), 3.11 (dd,J=16.29, 4.42 Hz, 1H), 3.80-3.88 (m, 2H), 3.90 (s, 3H), 3.94-4.05 (m,2H), 5.00 (dd, J=8.46, 4.42 Hz, 1H), 6.78 (d, J=8.34 Hz, 1H), 7.11 (d,J=7.33 Hz, 1H), 7.13-7.24 (m, 2H), 7.59 (dd, J=8.08, 5.81 Hz, 1H), 7.76(t, J=7.83 Hz, 1H). MS (ES) [M+H] calc'd for C₂₆H₃₀FN₆O₄, 509.22; found,509.20.

Example 61 5-(aminooxy)-2-methylpentane-2,3-diol

Route-A

To a solution of 5-bromo-2-methylpent-2-ene (1.33 mL, 10.0 mmol) inCH₃CN (25 mL) was added tert-butyl hydroxycarbamate (2.0 g, 15.0 mmol)and DBU (4.5 mL, 30 mmol) at 0° C. and the reaction mixture stirred atr.t. for overnight. Quenched with saturated NH₄Cl solution and extractedwith brine. Combined organic layers washed with brine and dried overanhydrous Na₂SO₄, filtered and concentrated to provide yellow oil, whichwas purified by flash chromatography (50% EtOAc-hexane) to yieldtert-butyl 4-methylpent-3-enyloxycarbamate (750 mg, 70%) as a viscousoil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 1.54 (s., 3H)1.61 (s., 3H) 2.21-2.31 (m, 2H) 3.70-3.78 (m, 2H) 5.02-5.10 (m, 1H). MS(ES) [M+H] calculated for C₁₁H₂₂NO₃, 216.15; found 216.10.

The resultant oily compound (750 mg, 3.5 mmol) was dissolved in 4:1dioxane-H₂O, NMO (409 mg, 3.85 mmol) and Os0₄ (0.2 mL, 0.35 mmol, 2.5 wt% in H₂O) was added. The reaction mixture was stirred for 24 h at rt.Work-up similar to the procedure described in Example 58 affordedtert-butyl 3,4-dihydroxy-4-methylpentyloxycarbamate (510 mg, 58%) as aviscous oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.14 (s, 3H) 1.20 (s, 3H)1.46 (s, 9H) 1.57-1.70 (m, 1H) 1.72-1.88 (m, 1H) 3.62-3.76 (m, 1H)3.92-4.15 (m, 2H). MS (ES) [M+H] calculated for C₁₁H₂₄NO₅, 250.15; found250.20.

The resultant oily compound (498 mg, 2.0 mmol) was dissolved in dioxane(2.0 ml) and cooled to 0° C. 4N HCl in dioxane (1.25 mL, 5.0 mmol) wasadded and the reaction mixture was stirred at ambient temperature for 2h. The resultant solid was filtered off and dried to afford the HCl saltof the title compound (260 mg, 70%) as white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ 1.16 (s, 3H) 1.19 (s, 3H) 1.63-1.71 (m, 1H) 1.98-2.06(m, 1H) 3.45 (d, J=12.88 Hz, 1H) 4.14-4.33 (m, 2H). MS (ES) [M+H]calculated for C₆H₁₆NO₃, 150.11; found 150.10.

Route-B

A mixture of 5-bromo-2-methylpent-2-ene (0.66 mL, 5.0 mmol) in CH₃CN (15mL) was added 2-hydroxyisoindoline-1,3-dione (3.33 g, 6.0 mmol) and DBU(4.5 mL, 30 mmol) was heated at 100° C. for 4 h. Work-up analogous tothe procedure described in Example 58 afforded2-(4-methylpent-3-enyloxy)isoindoline-1,3-dione (1.14 g, 90%) as aviscous oil.

The resultant compound was subjected for dihydroxylation followed byphthalimide deprotection analogous to the procedures described earlier(Example 57) afforded the title compound.

Example 62

-   (7R,    Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one    O-3,4-dihydroxy-4-methylpentyl oxime (Compound 60)

The title compound was prepared analogous to the procedure described inExample 58. ¹H NMR (400 MHz, MeOD) δ ppm 0.99 (d, J=5.31 Hz, 3H) 1.04(d, J=5.31 Hz, 3H) 1.34-1.51 (m, 1H) 1.92-2.07 (m, 1H) 2.53 (d, J=1.77Hz, 3H) 2.73-2.89 (m, 1H) 3.03 (dd, J=16.17, 5.05 Hz, 1H) 3.16-3.30 (m,1H) 3.86 (d, J=3.03 Hz, 3H) 3.95-4.06 (m, 2H) 4.93-5.13 (m, 1 H) 6.86(d, J=8.34 Hz, 1H) 7.19 (d, J=7.33 Hz, 1H) 7.22-7.34 (m, 2H) 7.41-7.56(m, 1H) 7.78-7.91 (m, 1H). MS (ES) [M+H] calc'd for C₂₆H₃₂FN₆O₄, 511.56;found 511.40.

Example 63(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (Compound 61)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588 mg,4.0 mmol), Hg(OAc)₂ (640 mg, 2.0 mmol) and toluene (5 mL) was heated at100° C. for 2 h. The mixture was cooled to r.t. and filtered throughcelite. Filtrate concentrated and the resulting oily residue wastriturated with dry methanol to afford a pale yellow solid. Filtered anddried to afford((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-ten-butyldimethylsilyloxime (384 mg, 80%) as a pale yellow solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s,9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36,4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td,J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72,5.94 Hz, 1 H). MS (ES) [M+H] calculated for C₂₀H₂₈BrFN₅OSi, 480.12;found 480.30.

A mixture of the above compound (47.9 mg, 0.1 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (149 mg, 0.5mmol), Pd(dppf)₂Cl₂ (8.12 mg, 0.01 mmol), 2N Na₂CO₃ (0.25 mL, 0.5 mmol)in DMA (3 mL) was degassed with N₂ and heated at 85° C. overnight. LCMSshows(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-ten-butyldimethylsilyl oxime ([M+H] calculated for C₂₆H₃₄BrFN₆O₂Si,509.24; found 509.40. The reaction mixture was diluted with ethylacetate and filtered through celite. The filtrate was concentrated toafford brown oil which was purified by preparative LCMS to afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (11.8 mg, 30%) as white solid.

Example 64(R)-4-0(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one(Compound 62)

A solution of (R)-3-tert-butyl 4-methyl2,2-dimethyloxazolidine-3,4-dicarboxylate (5 g, 19.3 mmol) in anhydrousdiethyl ether was chilled in an ice bath and 1 M LiAlH₄ in diethyl ether(38 mL, 38.6 mmol) was added dropwise under an N₂ atmosphere. Thereaction was allowed to warm to room temperature with stirringovernight. The reaction was quenched by slowly adding saturated aqueousNa₂SO₄ (5 mL). The slurry was filtered through a pad of Celite. TheCelite pad was rinsed with EtOAc and the solution was dried in vacuo toyield (S)-tert-butyl4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.77 g, 12mmol) as a clear oil. [M+H] calc'd for C₁₁H₂₁NO₄, 232; found, 232.

Standard Mitsunobu and hydrazine deprotection route to alkoxyamine wasused as described in Example 2. [M+H] calc'd for C₁₁H₂₂N₂O₄, 247; found,247.

Standard coupling to thiolactam scaffold via Hg(OAc)₂ was used asdescribed in Example 39. [M+H] calc'd for C₂₅H₃₂BrFN₆O₄, 580; found,580.

To a solution of (R)-tert-butyl44(Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-2,2-dimethyloxazolidine-3-carboxylatein dioxane was added 4 N HCl in dioxane. The reaction was allowed tostir under an N₂ atmosphere at room temperature for 90 min. The reactionwas lyophilized to dryness to yield(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2-amino-3-hydroxypropyl oxime (65 mg, 0.13 mmol). [M+H] calc'd forC₁₇H₂₀BrFN₆O₂, 440; found, 440.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2-amino-3-hydroxypropyl oxime (65 mg, 0.13 mmol) in anhydrousdichloromethane (3 mL) was added triethylamine (400 μL, 22 eq) andtriphosgene (94 mg, 0.33 mmol). The reaction was stirred under an N₂atmosphere at room temperature overnight. The reaction was washed withH₂O×1 and the organic phase dried over anhydrous Na₂SO₄. The solvent wasremoved in vacuo and the residue was purified via preparative HPLCeluting with TFA/ACN/H₂O to yield(R)-44(Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one(12 mg, 0.026 mmol). [M+H] calc'd for C₁₈H₁₈BrFN₆O₃, 466; found, 466.

Standard Suzuki conditions to attach pyridyl ring were used as describedin Example 39. ¹H NMR (400 MHz, MeOD) δ 2.76 (s, 3H), 3.03-3.19 (m, 1H),3.33-3.53 (m, 1H), 3.91 (s, 3H), 3.97-4.08 (m, 1H), 4.07-4.24 (m, 2H),4.29 (dd, J=8.72, 4.67 Hz, 1H), 4.42-4.55 (m, 1H), 5.05 (dd, J=8.97,4.17 Hz, 1H), 6.79 (d, J=8.34 Hz, 1H), 7.12 (d, J=7.33 Hz, 1H),7.14-7.29 (m, 2H), 7.66 (dd, J=8.59, 5.56 Hz, 1H), 7.77 (t, J=7.83 Hz,1H). [M+H] calc'd for C₂₄H₂₄FN₇O₄, 494; found, 494.

Example 65(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-morpholinoethyl oxime (Compound 63)

To a solution of 2-morpholinoethanol (5 g, 38 mmol) in CH₂Cl₂ (250 mL)was added 2-hydroxyisoindoline-1,3-dione (9.3 g, 57 mmol) andtriphenylphosphine (15 g, 57 mmol). The resultant mixture was cooled to0° C. and diisopropyl azodicarboxylate (11 ml, 57 mmol) was slowly addeddrop wise with an addition funnel under N₂ atmosphere. The reactionmixture was stirred at ambient temperature for 48 h. The reactionmixture was concentrated to provide clear oil, which was purified byflash chromatography (50% EtOAc—Hexane). The resultant clear oilycompound was dissolved in CH₂Cl₂ (50 ml). Hydrazine hydrate (5.8 mL, 76mmol) was added. The reaction mixture was stirred at ambient temperaturefor 8 h. The resultant solid was filtered off and the filtrateconcentrated under reduced pressure to provide a clear oil ofO-(2-morpholinoethyl)hydroxylamine (3.5 g, 24 mmol). [M+H] calc'd forC₆H₁₄N₂O₂, 147; found, 147.

To a solution of O-(2-morpholinoethyl)hydroxylamine (600 mg, 4.1 mmol)in anhydrous toluene (6 mL) was added(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(0.150 g, 0.41 mmol) and mercuric acetate (II) (262 mg, 0.82 mmol). Theresultant mixture was heated to 100° C. for 1 h. The reaction wasallowed to cool to r.t. and filtered through a pad of Celite, rinsingwith EtOAc and CH₃OH. The filtrate was concentrated to provide ayellow-green oil, which was purified by preparative HPLC eluting withTFA/ACN/H₂O. The fractions were concentrated to provide(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-morpholinoethyl oxime (196 mg, 0.41 mmol). [M+H] calc'd forC₂₀H₂₄BrFN₆O₂, 480; found, 480.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-morpholinoethyl oxime (100 mg, 0.21 mmol) in DMA was added6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester (250 mg,0.84 mmol), Pd(dppf)₂Cl₂ (17 mg, 0.02 mmol), and 2N Na₂CO₃ (522 μL, 1.05mmol). The resultant mixture was degassed with N₂ for 5 min then heatedin a sealed tube at 85° C. for 14 h. The reaction was allowed to cool tor.t. and filtered through a pad of Celite topped with anhydrous Na₂SO₄,rinsing with EtOAc and CH₃OH. The filtrate was concentrated to provide abrown residue which was purified by preparative HPLC eluting withTFA/ACN/H₂O. The solvent was removed on a rotary evaporator and thesample was dried under high vacuum to yield(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-morpholinoethyl oxime (67.4 mg, 0.13 mmol). ¹H NMR (400 MHz,CHLOROFORM-d) δ 2.81 (s, 3H), 2.95 (td, J=11.87, 3.79 Hz, 2H), 3.12 (dd,J=17.18, 9.60 Hz, 1H), 3.34-3.56 (m, 3H), 3.70 (dd, J=11.75, 3.41 Hz,2H), 3.84-4.06 (m, 7H), 4.39 (t, J=4.80 Hz, 2H), 4.94 (dd, J=9.60, 4.04Hz, 1H), 6.81 (d, J=8.34 Hz, 1H), 7.06 (d, J=7.07 Hz, 1H), 7.08-7.21 (m,2H), 7.50 (dd, J=8.59, 5.31 Hz, 1H), 7.68-7.81 (m, 1H). [M+H] calc'd forC₂₆H₃₀FN70₃, 508; found, 508.

Example 66(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(tetrahydro-2H-pyran-4-yl)methyl oxime (Compound 64)

A solution of methyl tetrahydro-2H-pyran-4-carboxylate (5 g, 34.6 mmol)in anhydrous diethyl ether was chilled in an ice bath and 1 M LiAlH₄ indiethyl ether (52 mL, 51.9 mmol) was added dropwise under an N₂atmosphere. The reaction was allowed to warm to room temperature withstirring overnight. The reaction was quenched by slowly adding 1 Naqueous NaOH (3 mL). The slurry was filtered through a pad of Celite.The Celite pad was rinsed with diethyl ether followed by methanol andthe solution was dried in vacuo to yield(tetrahydro-2H-pyran-4-yl)methanol (4 g, 34.6 mmol) as a clear oil.[M+H] calc'd for C₆H₁₂O₂, 117; found, 117.

Standard Mitsunobu/hydrazine deprotection route to alkoxyamine was usedas described in Example 2, [M+H] calc'd for C₆H₁₃NO₂, 132; found, 132.

Standard coupling to thiolactam scaffold via Hg(OAc)₂ was used asdescribed in Example 39. [M+H] calc'd for C₂₀H₂₃BrFN₅O₂, 465; found,465.

Standard Suzuki conditions to attach pyridyl ring were used as describedin Example 39. ¹H NMR (400 MHz, MeOD) δ 1.19-1.41 (m, 2H), 1.64 (d,J=12.88 Hz, 2H), 1.96-2.13 (m, 1H), 2.80 (s, 3H), 3.19 (dd, J=16.93,8.59 Hz, 1H), 3.33-3.47 (m, 3H), 3.84-4.00 (m, 7 H), 5.03-5.13 (m, 1H),6.80 (d, J=8.34 Hz, 1H), 7.12 (d, J=7.07 Hz, 1H), 7.15-7.27 (m, 2 H),7.60 (dd, J=8.34, 5.56 Hz, 1H), 7.77 (t, J=7.83 Hz, 1H). [M+H] calc'dfor C₂₆H₂₉FN₆O₃, 493; found, 493.

Example 67(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((1s,4S)-4-hydroxycyclohexyl)methyl oxime (Compound 65)

To a solution of (1r,4r)-4-hydroxycyclohexanecarboxylic acid (5 g, 34.7mmol) in anhydrous DMF (35 mL) was added imidazole (4.72 g, 69.4 mmol)and TBDMS chloride (5.75 g, 38.2 mmol). The reaction was allowed to stirunder an N₂ atmosphere at room temperature overnight. The reaction wasdiluted with diethyl ether and washed with 1 N aqueous HCl×2 thenbrine×1. The organic phase was dried over amhydrous Na₂SO₄ and thesolvent removed in vacuo to yield(1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylic acid (8.9 g,34.7 mmol) as a clear oil.

A solution of(1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexanecarboxylic acid (8.9 g,34.7 mmol) in anhydrous dichloromethane (80 mL) was chilled in a dryice/acetone bath and a 20 wt % solution of DIBAL-H in toluene (57 mL,69.4 mmol) was added dropwise under an N₂ atmosphere. The reaction wasallowed to warm to −30° C. with stirring over 1 h. The cold reactionmixture was slowly poured into chilled 1 N aqueous HCl (150 mL). Theaqueous phase is washed with DCM×2 and the combined organic phases werewashed with brine×1 and dried over anhydrous Na₂SO₄. The solvent wasremoved in vacuo to yield((1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (4.5 g, 18.4mmol).

To a solution of((1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexyl)methanol (4.5 g, 18.4mmol) in CH₂Cl₂ (150 mL) was added 2-hydroxyisoindoline-1,3-dione (4.5g, 27.6 mmol) and triphenylphosphine (7.25 g, 27.6 mmol). The resultantmixture was cooled to 0° C. and diisopropyl azodicarboxylate (5.35 ml,27.6 mmol) was slowly added drop wise with an addition funnel under N₂atmosphere. The reaction mixture was stirred at ambient temperature for48 h. The reaction mixture was concentrated to provide clear oil, whichwas purified by flash chromatography (50% EtOAc—Hexane). The resultantclear oily compound was dissolved in CH₂Cl₂ (50 ml). Hydrazine hydrate(1.47 mL, 19.3 mmol) was added. The reaction mixture was stirred atambient temperature for 8 h. The resultant solid was filtered off andthe filtrate concentrated under reduced pressure to provide a clear oilofO-(((1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexyl)methyl)hydroxylamine(2.5 g, 9.66 mmol). [M+H] calc'd for C₁₃H₂₉NO₂Si, 260; found, 260.

To a solution ofO-(((1r,4r)-4-(tert-butyldimethylsilyloxy)cyclohexyl)methyl)hydroxylamine(530 mg, 2.05 mmol) in anhydrous toluene (8 mL) was added(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(0.150 g, 0.41 mmol) and mercuric acetate (262 mg, 0.82 mmol). Theresultant mixture was heated to 100° C. for 1 h. The reaction wasallowed to cool to r.t. and filtered through a pad of Celite, rinsingwith EtOAc and CH₃OH. The filtrate was concentrated to provide ayellow-green oil, which was purified by preparative HPLC eluting withTFA/ACN/H₂O. Upon drying down the preparative HPLC fractions at 50° C.on a rotary evaporator, the alcohol was formed cleanly to provide(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((1s,4S)-4-hydroxycyclohexyl)methyl oxime (63 mg, 0.13 mmol). [M+H]calc'd for C_(2i)H₂₅BrFN₅O₂, 479; found, 479.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((1s,4S)-4-hydroxycyclohexyl)methyl oxime (63 mg, 0.13 mmol) in DMAwas added 6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester(157 mg, 0.52 mmol), Pd(dppf)₂Cl₂ (10.6 mg, 0.013 mmol), and 2N Na₂CO₃(329 μL, 0.65 mmol). The resultant mixture was degassed with N₂ for 5min then heated in a sealed tube at 85° C. for 14 h. The reaction wasallowed to cool to r.t. and filtered through a pad of Celite topped withanhydrous Na₂SO₄, rinsing with EtOAc and CH₃OH. The filtrate wasconcentrated to provide a brown residue which was purified bypreparative HPLC eluting with TFA/ACN/H₂O. The solvent was removed on arotary evaporator and the sample was dried under high vacuum to yield(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-((1s,4S)-4-hydroxycyclohexyl)methyl oxime (10 mg, 0.02 mmol). ¹H NMR(400 MHz, MeOD) δ 1.40-1.60 (m, 6H), 1.69 (dd, J=8.08, 4.55 Hz, 2H),1.77-1.92 (m, 1H), 2.73 (s, 3H), 3.05-3.18 (m, 1H), 3.21-3.28 (m, 1H),3.83-3.96 (m, 6H), 5.09 (dd, J=8.34, 4.55 Hz, 1H), 6.80 (d, J=8.34 Hz,1H), 7.12 (d, J=7.07 Hz, 1H), 7.15-7.25 (m, 2H), 7.58 (dd, J=8.34, 5.81Hz, 1H), 7.71-7.82 (m, 1H). [M+H] calc'd for C₂₇H_(3i)FN₆O₃, 507; found,507.

Example 68(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide(Compound 66)

To a solution of 3-hydroxydihydrofuran-2(311)-one (5 g, 49 mmol) inanhydrous DMF (50 mL) was added imidazole (6.7 g, 98 mmol) and TBDMSchloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N₂atmosphere at room temperature overnight. The reaction was diluted withdiethyl ether and washed with 1 N aqueous HC1×2 then brine×1. Theorganic phase was dried over Na₂SO₄ and the solvent removed in vacuo toyield 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(311)-one (11 g, 49mmol) as a clear oil. [M+H] calc'd for C₁₀H₂₀O₃Si, 217; found, 217.

To a solution of 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(311)-one(11 g, 49 mmol) in methanol was added 7 N ammonia in methanol (20 mL,140 mmol). The reaction was stirred in a sealed tube for 2 days. Thesolvent was removed in vacuo to yield(S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8mmol) as a white solid. [M+H] calc'd for C₁₀H₂₃NO₃Si, 234; found, 234.

To a solution of (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide(4.85 g, 20.8 mmol) in CH₂Cl₂ (150 mL) was added2-hydroxyisoindoline-1,3-dione (5.1 g, 31.2 mmol) and triphenylphosphine(8.2 g, 31.2 mmol). The resultant mixture was cooled to 0° C. anddiisopropyl azodicarboxylate (6.0 ml, 31.2 mmol) was slowly addeddropwise with an addition funnel under N₂ atmosphere. The reactionmixture was stirred at ambient temperature for 48 h. The reactionmixture was concentrated to provide clear oil, which was purified byflash chromatography (60% EtOAc—Hexane). The resultant pale yellowcompound was dissolved in CH₂Cl₂ (60 ml). Hydrazine hydrate (670 μL, 8.8mmol) was added. The reaction mixture was stirred at ambient temperaturefor 8 h. The resultant solid was filtered off and the filtrateconcentrated under reduced pressure to provide a clear yellow oil of(S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1.1 g, 4.4mmol). [M+H] calc'd for C₁₀H₂₄N₂O₃Si, 249; found, 249.

To a solution of(S)-4-(aminooxy)-2-(tert-butyldimethylsilyloxy)butanamide (1 g, 4.1mmol) in anhydrous toluene (10 mL) was added(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(0.300 g, 0.82 mmol) and mercuric (II) acetate (523 mg, 1.64 mmol). Theresultant mixture was heated to 100° C. for 2 h. The reaction wasallowed to cool to r.t. and filtered through a pad of Celite, rinsingwith EtOAc and CH₃OH. The filtrate was concentrated to provide ayellow-green oil, which was purified by preparative HPLC eluting withTFA/ACN/H₂O. Upon drying down the preparative HPLC fractions at 50° C.on a rotary evaporator, the alcohol was formed cleanly to provide(S)-4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide(51 mg, 0.11 mmol). [M+H] calc'd for C₁₈H₂₀BrFN₆O₃, 477; found, 477.

To a solution of(S)-4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide(51 mg, 0.11 mmol) in DMA was added 6-methoxypyridine-2-boronic acidN-phenyldiethanolamine ester (130 mg, 0.44 mmol), Pd(dppf)₂Cl₂ (9 mg,0.011 mmol), and 2N Na₂CO₃ (273 μL, 0.55 mmol). The resultant mixturewas degassed with N₂ for 5 min then heated in a sealed tube at 85° C.for 14 h. The reaction was allowed to cool to r.t. and filtered througha pad of Celite topped with anhydrous Na₂SO₄, rinsing with EtOAc andCH₃OH. The filtrate was concentrated to provide a brown residue whichwas purified by preparative HPLC eluting with TFA/ACN/H₂O. The solventwas removed on a rotary evaporator and the sample was dried under highvacuum to yield(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide(12.6 mg, 0.025 mmol). ¹H NMR (400 MHz, MeOD) δ 1.76-1.93 (m, 1H),2.16-2.35 (m, 1H), 2.80 (s, 3H), 3.18 (dd, J=16.80, 9.22 Hz, 1H),3.32-3.42 (m, 1H), 3.90 (s, 3H), 4.10 (dd, J=8.72, 3.16 Hz, 1H),4.13-4.31 (m, 2H), 5.07 (dd, J=9.09, 4.04 Hz, 1H), 6.79 (d, J=8.08 Hz,1H), 7.12 (d, J 7.33 Hz, 1H), 7.15-7.28 (m, 2H), 7.66 (dd, J=8.59, 5.56Hz, 1H), 7.71-7.83 (m, 1H).

[M+H] calc'd for C₂₄H₂₆PN₇O₄, 496; found, 496.

Example 69(7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-(morpholin-2-yl)ethyl oxime (Compound 67)

¹H NMR (400 MHz, MeOD) δ 1.75-1.92 (m, 1H), 1.91-2.08 (m, 1H), 2.78 (s,3H), 2.90 (t, J=11.87 Hz, 1H), 3.03-3.18 (m, 1H), 3.18-3.28 (m, 2H),3.32-3.42 (m, 2H), 3.68-3.85 (m, 2H), 3.91 (s, 3H), 4.02 (d, J=12.88 Hz,1H), 4.07-4.28 (m, 2H), 5.01-5.11 (m, 1 H), 6.81 (d, J=8.34 Hz, 1H),7.13 (d, J=7.07 Hz, 1H), 7.16-7.35 (m, 2H), 7.56-7.69 (m, 1 H), 7.78 (t,J=7.83 Hz, 1H). [M+H] calc'd for C₂₆H₃₀FN₇O₃, 508; found, 508.

Example 70(S)-4-4(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)-3-benzyloxazolidin-2-one(Compound 68)

¹H NMR (400 MHz, CHLOROFORM-d) δ 2.48-2.65 (m, 3H), 2.97-3.16 (m, 1H),3.19-3.35 (m, 1H), 3.88 (s, 3H), 3.90-3.99 (m, 1H), 4.00-4.16 (m, 2H),4.15-4.27 (m, 1 H), 4.26-4.39 (m, 1H), 4.72-4.86 (m, 1H), 4.90 (dd,J=10.23, 3.41 Hz, 1H), 5.47-5.63 (m, 1H), 6.74 (d, J=8.34 Hz, 1H),6.97-7.06 (m, 1H), 7.10-7.21 (m, 2H), 7.20-7.26 (m, 5H), 7.57-7.71 (m,2H). [M+H] calc'd for C₃₁H₃₀PN₇O₄, 584; found, 584.

Example 71(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2-amino-3-hydroxypropyl oxime (Compound 69)

¹H NMR (400 MHz, MeOD) δ 2.81 (s, 3H), 2.90-3.00 (m, 1H), 3.02-3.16 (m,1H), 3.69-3.78 (m, 1H), 3.82 (dd, J=11.37, 3.54 Hz, 2H), 3.91 (s, 3H),4.13-4.34 (m, 2H), 5.03-5.10 (m, 1H), 6.72-6.92 (m, 1H), 7.13 (d, J=7.07Hz, 1H), 7.16-7.34 (m, 2H), 7.63-7.75 (m, 1H), 7.79 (t, J=7.71 Hz, 1H).[M+H] calc'd for C₂₃H₂₆FN₇O₃, 468; found, 468.

Example 72(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(1-methyl-1H-imidazol-4-yl)methyl oxime (Compound 70)

¹H NMR (400 MHz, MeOD) δ 2.71 (s, 3H), 3.18 (dd, J=16.80, 9.22 Hz, 1H),3.34-3.43 (m, 1H), 3.87 (s, 3H), 3.92 (s, 3H), 5.06-5.11 (m, 3H), 6.80(d, J=8.34 Hz, 1H), 7.12 (d, J=7.33 Hz, 1H), 7.15-7.29 (m, 2H),7.53-7.67 (m, 2H), 7.67-7.85 (m, 1H), 8.85 (br. s., 1H). [M+H] calc'dfor C₂₅H₂₅FN₈O₂, 489; found, 489.

Example 73(R)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-5-imino-4-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine(Compound 71)

¹H NMR (400 MHz, MeOD) δ 2.56-2.66 (m, 3H), 3.28 (d, J=7.83 Hz, 2H),3.88 (s, 3H), 5.32 (t, J=7.83 Hz, 1H), 6.75-6.86 (m, 1H), 7.11-7.22 (m,1H), 7.23-7.36 (m, 2H), 7.72 (t, J=6.82 Hz, 1H), 7.74-7.84 (m, 1H).[M+H] calc'd for C₂₀H₁₉PN₆O, 379; found, 379.

Example 74(R,Z)-2-amino-7-(2-(5-amino-6-methoxypyrazin-2-yl)-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 72)

¹H NMR (400 MHz, DMSO-d₆) δ 1.44-1.61 (m, 1H), 1.78-1.95 (m, 1H), 2.53(s, 3 H), 2.86 (dd, J=16.04, 7.45 Hz, 1H), 3.08 (dd, J=15.92, 4.80 Hz,1H), 3.20-3.30 (m, 2H), 3.47-3.58 (m, 1H), 3.89 (s, 3H), 3.96-4.07 (m,2H), 4.40-4.51 (m, 2H), 4.95-5.06 (m, 1 H), 6.22 (d, J=1.52 Hz, 1H),6.54 (s, 2H), 6.78 (s, 2H), 7.13-7.29 (m, 2H), 7.45 (dd, J=8.46, 5.94Hz, 1H), 7.70 (s, 1H). [M+H] calc'd for C₂₃H₂₇PN₈O₄, 499; found, 499.

Example 75(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyrazin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 73)

¹H NMR (400 MHz, MeOD) δ 1.59-1.74 (m, 1H), 1.88-2.06 (m, 1H), 2.62 (s,3H), 3.02 (dd, J=16.29, 9.22 Hz, 1H), 3.13-3.25 (m, 1H), 3.39-3.53 (m,2H), 3.67-3.78 (m, 1 H), 3.97 (s, 3H), 4.06-4.24 (m, 2H), 4.89-4.94 (m,1H), 7.20-7.33 (m, 2H), 7.63-7.74 (m, 1H), 8.21 (s, 1H), 8.32 (s, 1H).[M+H] calc'd for C₂₃H₂₆PN₇O₄, 484; found, 484.

Example 76(R,Z)-2-amino-7-(4-fluoro-2-(2-methoxythiazol-4-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime (Compound 74)

¹H NMR (400 MHz, MeOD) 61.61-1.75 (m, 1H), 1.91-2.06 (m, 1H), 2.63 (s,3H), 2.95 (dd, J=16.17, 8.08 Hz, 1H), 3.21 (dd, J=16.17, 4.80 Hz, 1H),3.40-3.53 (m, 2H), 3.69-3.79 (m, 1H), 4.08 (s, 3H), 4.11-4.22 (m, 2H),5.06 (dd, J=7.71, 4.93 Hz, 1H), 7.00 (s, 1H), 7.10 (td, J=8.46, 2.78 Hz,1H), 7.22 (dd, J=9.60, 2.78 Hz, 1H), 7.48 (dd, J=8.72, 5.68 Hz, 1 H).[M+H] calc'd for C₂₂H₂₅PN₆O₄S, 489; found, 489.

Example 77 Synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyridol[4,3-d]pyrimidin-5(6H)-oneO—(S)-4,5-dihydroxypentyl oxime (Compound 75)

Compound A was synthesized as previously reported (70.7% yield) ¹H NMR(400 MHz, CHLOROFORM-d) δ 1.36 (s, 3H), 1.41 (s, 3H), 1.71-2.01 (m, 4H),3.43-3.67 (m, 1 H), 4.05-4.10 (m, 1H), 4.16-4.31 (m, 3H), 7.70-7.79 (m,2H), 7.80-7.91 (m, 2H).

Compound B((S)—O-(3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl)hydroxylamine) wassynthesized as previously reported on similar chemistry, quantitativeyield. ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.36 (s, 3H), 1.41 (s, 3H),1.57-1.76 (m, 4H), 3.50-3.55 (m, 1H), 3.69 (td, J=6.13, 2.65 Hz, 2H),4.02-4.07 (m, 1H), 4.07-4.16 (m, 1H), 5.36 (s, 2H).

Compound C was also prepared as described before. ESI-MS: m/z 508.2(M+H)⁺. Purification by prep TFA method deprotected the acetonide groupand gave compound D (55.1% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.21-1.37(m, 1H), 1.47-1.60 (m, 1H), 1.68 (ddd, J=13.01, 10.11, 5.94 Hz, 1H),1.73-1.91 (m, 1H), 2.61 (s, 3H), 2.87 (dd, J=16.17, 4.29 Hz, 1H),3.16-3.33 (m, 3H), 3.35-3.50 (m, 1H), 3.87-4.07 (m, 3H), 4.89-5.00 (m,2H), 6.91 (br. s., 1H), 7.14-7.26 (m, 3H), 7.58 (dd, J=8.46, 2.40 Hz,1H).

Suzuki's coupling of compound D with the usual procedure providedcompound 75 (19.3% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.16-1.33 (m,2H), 1.48 (d, J=4.55 Hz, 1 H), 1.62 (br. s., 1H), 1.76 (d, J=10.36 Hz,1H), 2.52 (s, 3H), 2.80 (dd, J=16.04, 6.95 Hz, 1 H), 2.97-3.07 (m, 1H),3.18-3.29 (m, 2H), 3.41 (br. s., 2H), 3.86 (s, 3H), 3.87-3.98 (m, 2 H),4.40 (br. s., 2H), 4.97-5.15 (m, 1H), 6.19-6.39 (m, 1H), 6.78 (s, 2H),6.85 (d, J=8.34 Hz, 1H), 7.19 (d, J=6.57 Hz, 1H), 7.21-7.30 (m, 2H),7.47 (dd, J=8.46, 5.94 Hz, 1H), 7.84 (dd, J=8.34, 7.33 Hz, 1H).

Example 78(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3-amino-2-hydroxypropyl oxime (Compound 76)

Compound F: ¹H NMR (400 MHz, CHLOROFORM-d) δ 1.26 (s, 9H), 1.28 (s, 6H),3.65-3.74 (m, 2H), 3.89-3.93 (m, 1H), 4.12 (m, 1H), 4.28-4.41 (m, 1H),5.58 (br. s., 2H).

Compound G was synthesized as described above. ESI-MS: m/z 579.1 (M+H)⁺.

Purification of G by LC/MS gradient 35-60% ACN in H₂O with TFA systemdeprotected the acetonide group to give compound H after evaporationstep. ESI-MS: m/z 539.2 (M+H)⁺, 20.8% yield over 2 steps.

Suzuki's coupling of H produced compound I. ESI-MS: m/z 568.3 (M+H)⁺,which was then deprotected with 20% TFA in dichloromethane for 45minutes to give product Compound 76.

Compound 76 was purified by basic mode, gradient 25-50% ACN in H₂O,46.1% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 2.52 (s, 3H), 2.69-2.86 (m,2H), 3.05 (d, J=4.55 Hz, 2H), 3.85 (s, 3H), 3.88 (dd, J=5.81, 3.79 Hz,2H), 3.98 (br. s., 2H), 5.02 (br. s., 1H), 5.05 (br.s., 2H), 6.59 (d,J=1.77 Hz, 1H), 6.86 (d, J=7.58 Hz, 1H), 7.18 (d, J=7.33 Hz, 1H), 7.28(ddd, J=5.68, 2.78, 2.65 Hz, 2H), 7.52 (dd, J=8.59, 5.81 Hz, 1H), 7.75(br. s., 2H), 7.84 (dd, J=8.34, 7.33 Hz, 1H).

Example 79(S)-5-4(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)methyl)oxazolidin-2-one(Compound 77)

Compound H was deprotected with 20% TFA in dichloromethane for 10minutes to give compound K, ESI-MS: m/z 439.1 (M+H)⁺.

Compound K was reacted with triphosgene, triethylamine indichloromethane as described previously to give compound L. It waspurified by preparative LC/MS, gradient 25-50% ACN in H₂O, 10.6% yield,ESI-MS: m/z 439.2 (M+H)⁺.

Suzuki's coupling of compound K with the normal procedure providedcompound 77, 32.7% yield. ¹H NMR (400 MHz, MeOD) δ 2.92 (s, 3H),3.35-3.40 (m, 1H), 3.44-3.52 (m, 1 H), 3.55-3.59 (m, 1H), 3.63-3.66 (m,1H), 3.91 (s, 3H), 4.20 (dd, J=6.44, 4.67 Hz, 2H), 4.95 (m, 1H), 5.05(m, 1H), 6.79 (d, J=8.34 Hz, 1H), 7.11 (d, J=6.57 Hz, 1H), 7.14-7.25 (m,2 H), 7.59 (m, 1H), 7.76 (dd, J=8.46, 7.20 Hz, 1H).

Example 80(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-3-hydroxypropyl oxime (Compound 78)

Compound 3 as prepared by procedure described above, 78.7% yield. ¹H NMR(400 MHz, CHLOROFORM-d) δ 0.08 (s, 6H), 0.84-0.93 (m, 9H), 1.99 (s, 2H),3.76-3.90 (m, 2 H), 4.27-4.39 (m, 2H), 7.70-7.78 (m, 2H), 7.80-7.88 (m,2H).

Compound 4 as prepared by procedure described above, 93.2% yield. ¹H NMR(400 MHz, CHLOROFORM-d) δ 0.05-0.09 (m, 6H), 0.84-0.95 (m, 9H),1.73-1.86 (m, 2H), 3.69 (t, J=6.19 Hz, 2H), 3.75 (t, J=6.32 Hz, 2H),5.34 (s, 2H).

Compound 6: ESI-MS: m/z 538.3 (M+H)⁺. Purification was done bypreparative LC/MS, using gradient 50-85% ACN in H₂O with TFA system.After evaporation compound 7 was obtained, 42.5% yield over 2 step,ESI-MS: m/z 424.2 (M+H)⁺.

Compound 78, LC/MS purification using basic mode, gradient 40-60% ACN inH₂O, 45.9% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 1.77 (quin, J=6.44 Hz,2H), 2.53 (s, 3H), 2.82 (dd, J=16.29, 7.20 Hz, 1H), 3.04 (dd, J=16.17,5.05 Hz, 1H), 3.42-3.54 (m, 2H), 3.86 (s, 3H), 3.91-4.04 (m, 2H),4.97-5.13 (m, 1H), 6.37 (br. s., 1H), 6.85 (d, J=7.58 Hz, 1H), 6.90 (br.S., 2H), 7.19 (d, J=6.82 Hz, 1H), 7.21-7.33 (m, 2H), 7.47 (dd, J=8.46,5.94 Hz, 1H), 7.84 (dd, J=8.34, 7.33 Hz, 1H).

Example 81(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-4-hydroxybutyl oxime (Compound 79)

Compound 81c as prepared by the procedure described above, 88.0% yield.¹H NMR (400 MHz, CHLOROFORM-d) δ 0.03-0.07 (m, 6H), 0.82-0.96 (m, 9H),1.74 (d, J=8.84 Hz, 2H), 1.86 (d, J=8.34 Hz, 2H), 3.69 (t, J=6.19 Hz,2H), 4.24 (t, J=6.57 Hz, 2H), 7.75 (dd, J=5.56, 3.03 Hz, 2H), 7.80-7.87(m, 2H).

Compound 81d as prepared by the procedure described above, 94.5% yield.¹H NMR (400 MHz, CHLOROFORM-d) δ 0.060 (s, 6H), 0.85-0.94 (m, 9H),1.51-1.59 (m, 3H), 1.59-1.69 (m, 2H), 3.63 (t, J=6.32 Hz, 2H), 3.65-3.72(m, 2H), 5.35 (s, 2H).

Compound 81f as prepared by the procedure described above. ESI-MS: m/z554.3 (M+H)⁺. Purification by LC/MS using the TFA system of gradient60-90% ACN/H₂O deprotected the TBDMS group to give compound 15, 22.2%yield over 2 steps. ESI-MS: m/z 438.1 (M+H)⁺.

Compound 79 as prepared by the procedure described above. The productwas purified by the basic mode, gradient 35-65% ACN/H₂O, 19.2% yield. ¹HNMR (400 MHz, DMSO-d₆) δ 1.37-1.56 (m, 2H), 1.56-1.74 (m, 2H), 2.53 (s,3H), 2.81 (dd, J=16.04, 7.20 Hz, 1H), 3.03 (dd, J=16.17, 5.05 Hz, 1H),3.40 (t, J=6.44 Hz, 2H), 3.92 (s, 3H), 3.88-3.98 (m, 2H), 5.05 (br. s.,1H), 6.31 (br. s., 1H), 6.85 (d, J=8.34 Hz, 3H), 7.19 (d, J=6.57 Hz, 1H), 7.22-7.32 (m, 2H), 7.47 (dd, J=8.46, 5.94 Hz, 1H), 7.84 (dd, J=8.34,7.33 Hz, 1H).

Example 82(7R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-3-hydroxy-2-methoxypropyl oxime (Compound 80)

Compound N: ESI-MS: m/z 122.0 (M+H)⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ3.33 (s, 3H), 3.40-3.46 (m, 3H), 3.67-3.75 (m, 1H), 3.75-3.83 (m, 1H),4.07 (m, 1H), 5.52 (br. s., 2H).

Compound O: purified by preparative LC/MS, gradient 25-55% ACN in H₂O,4.9% yield, ESI-MS: m/z 454.3 (M+H)⁺.

Compound 80: purified by preparative LC/MS, basic mode, gradient 30-70%ACN in H₂O, 16.1% yield. ¹H NMR (400 MHz, MeOD) δ 2.61 (s, 3H),2.89-3.05 (m, 1H), 3.07-3.21 (m, 1H), 3.34 (d, J=2.02 Hz, 3H), 3.37-3.50(m, 2H), 3.61-3.75 (m, 1H), 3.89 (s, 3H), 3.92-4.01 (m, 1H), 4.01-4.09(m, 2H), 4.93-5.03 (m, 1H), 6.78 (d, J=8.34 Hz, 1H), 7.11 (d, J=7.07 Hz,1H), 7.13-7.25 (m, 2H), 7.64 (dd, J=8.46, 5.68 Hz, 1H), 7.75 (t, J=7.83Hz, 1H).

Example 83(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yflphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-4,5-dihydroxypentyl oxime (Compound 81)

Compound 83b as prepared by a procedure described above. ¹H NMR (400MHz, CHLOROFORM-d) δ 1.36 (s, 3H), 1.39-1.45 (s, 3H), 1.73-2.00 (m, 4H),2.05 (s, 1H), 3.54-3.63 (m, 1H), 4.04-4.14 (m, 1H), 4.14-4.21 (m, 1H),4.21-4.33 (m, 2H), 7.72-7.79 (m, 2 H), 7.81-7.87 (m, 2H).

Compound 83c as prepared by a procedure described above, 88.2% yieldover 2 steps. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.36 (s, 3H), 1.41 (s,3H), 1.59-1.78 (m, 4H), 3.50-3.55 (m, 1H), 3.69 (td, J=6.25, 2.40 Hz,2H), 4.01-4.07 (m, 1H), 4.11 (dd, J=7.07, 5.56 Hz, 1H), 5.36 (s, 2H).

Compound 83d: ESI-MS: m/z 508.3 (M+H)⁺. LC/MS purification usinggradient 40-60% ACN in H2O (TFA method) gave compound 5, ESI-MS: m/z468.1 (M+H)⁺, 24.1% yield over 2 steps.

Compound 81, purification was done by both the basic mode and acidicmode, 21.6% yield, ¹H NMR (400 MHz, MeOD) δ 1.35-1.52 (m, 1H), 1.59 (dt,J=10.04, 4.07 Hz, 1H), 1.74 (ddd, J=13.71, 10.04, 6.06 Hz, 1H),1.82-2.08 (m, 1H), 3.14 (dd, J=16.67, 8.84 Hz, 1 H), 3.28-3.35 (m,J=4.55 Hz, 1H), 3.38-3.49 (m, 2H), 3.54-3.68 (m, 1H), 3.84-3.97 (s, 3H), 4.06 (t, J=6.44 Hz, 2H), 5.08 (dd, J=8.84, 4.29 Hz, 1H), 6.79 (d,J=7.58 Hz, 1H), 7.12 (d, J=6.57 Hz, 1H), 7.15-7.24 (m, 2H), 7.62 (dd,J=8.59, 5.56 Hz, 1H), 7.76 (dd, J=8.34, 7.33 Hz, 1H).

Example 84 (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane

To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1.58 mL,10.0 mmol) in CH₂Cl₂ (25 mL) was added DMAP (120 mg, 1.0 mmol) andtriethylamine (2.08 mL, 15.0 mmol). The reaction mixture was cooled to 0‘C and methanesulfonyl chloride (12.0 mmol, 0.928 mL) was added slowlydropwise under N₂ atmosphere. The reaction mixture was stirred for 2 h(monitored by TLC, 1:2 EtOAc—Hexanes). Saturated NH₄Cl solution (20 mL)was added and the mixture was extracted with CH₂Cl₂. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated to provide a yellow oil, which was dissolvedin dry acetone (25 ml), followed by addition of NaI (7.5 g, 50 mmol).The reaction mixture was refluxed for 2 h (monitored by TLC, 1:4EtOAc—Hexanes), cooled to room temperature and water (50 mL) was added.Extraction with ethyl acetate, washing of the combined organic layerswith brine, drying over anhydrous Na₂SO₄, filtration and concentrationprovided a yellow oil, which was purified by flash chromatography (25%EtOAC-Hexane) to afford the title compound,(S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (0.82 g, 32% over twosteps) as a clear oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s,3H), 1.41 (s, 3H), 1.99-1.16 (m, 2H), 3.25 (dd, J=18.19, 8.84 Hz, 2H),3.58 (t, J=7.20 Hz, 1H), 4.03-4.13 (m, 1 H), 4.13-4.24 (m, 1H). MS (ES)[M+H] calculated for C₂H₁₄IO₂, 257.00; found 257.08.

Example 85 Alternative synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (Compound 37)

Compound 2K was prepared as previously described. A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(2K, 366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (85a,588 mg, 4.0 mmol), Hg(0Ac)_(z) (640 mg, 2.0 mmol) and toluene (5 mL) washeated at 100° C. for 2 h. The mixture was cooled to room temperatureand filtered through Celite. The filtrate was concentrated and theresulting oily residue was triturated with dry methanol to afford, afterfiltration and drying,(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (384 mg, 80%) as a pale yellow solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H) 0.97 (s,9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd, J=16.36,4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05 (td,J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd, J=8.72,5.94 Hz, 1 H). MS (ES) [M+H] calculated for C₂₀H₂₈BrFN₅OSi, 480.12;found 480.30.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (85b, 384 mg, 0.8 mmol) in dioxane (2 mL)was added 1:9 TFA-H₂O and the reaction mixture stirred at roomtemperature for 2 h. The resulting solid was filtered and washed withdioxane, then dried to afford(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (85c, 206 mg, 70%) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.56 (s, 3H) 2.83 (dd, J=15.92, 4.55 Hz, 1H) 3.17 (dd,J=16.04, 5.94 Hz, 1H) 4.90 (q, J=4.97 Hz, 1H) 7.20 (d, J=1.52 Hz, 1H)7.21-7.23 (m, 1H) 7.57 (ddd, J=8.34, 1.64, 1.39 Hz, 1 H) 9.82 (s, 1H).MS (ES) [M+H] calculated for C₁₄H₁₄BrFN₅O, 366.03; found 366.20.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (85c, 9.2 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs₂CO₃ (12.2mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperaturefor 30 minutes. Then, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane(85d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirredovernight. LCMS showed complete consumption of the starting material.The reaction mixture was poured onto crushed ice and the resulting solidwas filtered and rinsed with cold water. Drying afforded(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (7.8 mg, 63%) as alight brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 3H)1.41 (s, 3H) 2.02 (qd, J=6.32, 3.03 Hz, 2H) 2.75 (s, 3H) 2.94 (dd,J=16.42, 8.84 Hz, 1H) 3.17 (dd, J=16.42, 4.55 Hz, 1H) 3.59 (dd, J=8.08,7.07 Hz, 1H) 4.09 (dd, J=8.08, 6.06 Hz, 1H) 4.17-4.28 (m, 3H) 4.98 (ddd,J=8.72, 4.55, 1.64 Hz, 1 H) 7.07 (td, J=8.27, 2.65 Hz, 1H) 7.34 (dd,J=8.08, 2.78 Hz, 1H) 7.43 (dd, J=8.72, 5.94 Hz, 1 H). MS (ES) [M+H]calculated for C₂₁H₂₇BrFN₅O₃, 495.11; found 495.30.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (85e, 1 g, 2 mmol)in 3N aq HCl (10 mL) and the reaction mixture stirred at ambienttemperature for 1 h. LCMS shows complete consumption of the startingmaterial. The resulting solid was filtered, washed with cold 1N HCl, anddried to afford(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (deprotected 85e, 603 mg, 65%) as anoff-white solid. MS (ES) [M+H] calculated for C₁₈H₂₂BrFN₅O₃, 454.08;found 454.02.

A mixture of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (deprotected 85e, 480 mg, 1.05 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.57 g, 5.25mmol), Pd(dppf)₂Cl₂ (0.086 g, 0.1 mmol), and 2N Na₂CO₃ (2.64 mL, 5.25mmol) in DMAc (5 mL) was degassed with N₂ and heated at 85° C.overnight. The reaction mixture was cooled to ambient temperature,diluted with ethyl acetate and filtered through Celite. The filtrate wasconcentrated to afford a brown oil, which was purified by preparativeLCMS (NH₄HCO₃/ACN/H₂O) to afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (Compound 37, 375 mg, 73%) as a lightbrown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.55 (m, 1H) 1.66(m, 1H) 2.55 (s, 3H) 2.83-2.95 (m, 2H) 3.11-3.44 (m, 1H) 3.17-3.24 (m,1H) 3.27-3.33 (m, 1H) 3.48-3.56 (m, 1H) 3.65 (s, 3H) 3.89-4.01 (m, 2H)4.68 (ddd, J=10.23, 3.03, 2.91 Hz, 1H) 6.53 (dd, J=8.34, 2.53 Hz, 1H)6.81 (dd, J=7.33, 2.53 Hz, 1H) 6.90 (dt, J=9.28, 2.68 Hz, 1H) 6.96 (td,J=8.40, 2.65 Hz, 1H) 7.38-7.43 (m, 1H) 7.44-7.51 (m, 1H). MS (ES) [M+H]calculated for C₂₄H₂₈FN₆O₄, 483.21; found 483.00.

Example 86 Second alternative synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (Compound 37)

Compound 86b was prepared as described in Example 85 above. Coupling of86f to 86b was prepared by both Method A and Method B.

Method A: A mixture of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (86b, 47.9 mg, 0.1 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (86f, 149 mg,0.5 mmol), Pd(dppf)Cl₂ (8.12 mg, 0.01 mmol), and 2N Na₂CO₃ (0.25 mL, 0.5mmol) in DMA (3 mL) was degassed with N₂ and heated at 85° C. overnight.LCMS showed consumption of starting material and formation of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyl oxime (86g or

61). ([M+H] calculated for C₂₆H₃₄BrFN₆O₂Si, 509.24; found 509.40).

The reaction mixture was diluted with ethyl acetate and filtered throughCelite. The filtrate was concentrated to afford a brown oil, which waspurified by preparative HPLC. During this purification thetert-butyldimethylsilyl protecting group was cleaved as well, thusaffording(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (37, 11.8 mg, 30%) as a white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.78 (s, 3H) 3.14-3.31 (m, 1H) 3.43-3.46 (m, 1H)3.89 (s, 3H) 5.08 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.34 Hz, 1H) 7.05 (d,J=7.07 Hz, 2H) 7.18 (d, J=8.84, 2H) 7.70 (t, J=7.71, 1H). MS (ES) [M+H]calculated for C₂₀H₂₀FN₆O₂, 395.16; found 395.20.

Method B:(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (Compound 86c) was prepared as described in Example 85 above. Amixture of 86c (36.5 mg, 0.1 mmol and2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (86f, 149 mg,0.5 mmol), Pd(dppf)₂Cl₂ (8.12 mg, 0.01 mmol), and 2N Na₂CO₃ (0.25 mL,0.5 mmol) in DMA (3 mL) was degassed with N₂ and heated at 85° C.overnight. The reaction mixture was cooled to ambient temperature,diluted with ethyl acetate and filtered through Celite. The filtrate wasconcentrated to afford brown oil which was purified by preparative HPLCto afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (86g or 61), 13.2 mg, 33%) as white solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.78 (s, 3H) 3.14-3.31 (m, 1H) 3.43-3.46 (m, 1H)3.89 (s, 3H) 5.08 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.34 Hz, 1H) 7.05 (d,J=7.07 Hz, 2H) 7.18 (d, J=8.84, 2H) 7.70 (t, J=7.71, 1H). MS (ES) [M+H]calculated for C₂₀H₂₀FN₆O₂, 395.16; found 395.20.

To a solution of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (86g or Compound 61, 10.0 mg, 0.025 mmol) in dry DMF (1 mL) wasadded Cs₂CO₃ (12.2 mg, 0.0375 mmol) and the reaction mixture stirred atambient temperature for 30 minutes. Then,(5)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (86d, 7.68 mg, 0.03 mmol)was added and the reaction mixture stirred overnight. LCMS showedcomplete consumption of starting material. The reaction mixture waspoured onto crushed ice and the resulting solid was filtered, rinsedwith cold water, and dried to afford(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (86h, 8.2 mg, 63%)as a light brown solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s,3H) 1.39 (s, 3 H) 1.91-2.01 (m, 4H) 2.72 (s, 3H) 3.07 (dd, J=16.55,10.48 Hz, 1H) 3.26 (dd, J=17.05, 4.93 Hz, 1H) 3.55 (dd, J=7.96, 7.20 Hz,1H) 3.90 (s, 3H) 4.05 (dd, J=7.96, 5.94 Hz, 1H) 4.10-4.21 (m, 3H) 4.89(dd, J=10.61, 3.79 Hz, 1H) 6.74 (d, J=8.84 Hz, 1H) 7.01 (d, J=8.08 Hz,1H) 7.11-7.22 (m, 2H) 7.61-7.69 (m, 2H)MS (ES) [M+H] calculated forC₂₂H₃₂FN₆O₄, 523.24; found 523.50.

Deprotection of 86h was achieved by treating with diluted HCl asdescribed in Example 85 to yield Compound 37.

Example 87(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methylacetamide(Compound

A. Synthesis of 2-(aminooxy)-N-methylacetamide (87c)

A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine(863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) wereadded sequentially. The mixture was stirred under an N₂ atmosphere for20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46mmol) was added to the reaction which was subsequently allowed to warmto room temperature with stirring overnight. The THF was removed invacuo and the residue was partitioned between ethyl acetate and water.The organic phase was washed with H₂O×2 and dried over anhydrous Na₂SO₄.The ethyl acetate was removed in vacuo to yield tert-butyl2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol).

To a slurry of tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87c, 775mg, 3.80 mmol) in anhydrous dioxane was added 4N HCl in dioxane (3 mL,12 mmol). The reaction was allowed to stir at room temperature under anN₂ atmosphere for 5 h. The reaction was freeze-dried and the residue wastaken up in 20% triethylamine in ethyl acetate to neutralize the HClsalt. The slurry was stirred for 1 h and the solvents were removed invacuo to yield a mixture of 2-(aminooxy)-N-methylacetamide (87c) andtriethylammonium chloride salt.

B. Preparation of Compound 82

The titled compound 82 was prepared by a procedure analogous to Example68, coupling of 2-(aminooxy)-N-methylacetamide (87c) was via Hg(OAc)₂.¹H NMR (400 MHz, MeOD) δ 2.75 (s, 3H), 2.76 (s, 3H), 3.19 (dd, J=16.67,9.35 Hz, 1H), 3.41 (dd, J=16.80, 4.17 Hz, 1H), 3.91 (s, 3H), 4.47 (s,2H), 5.06 (dd, J=9.35, 4.04 Hz, 1H), 6.80 (d, J=8.34 Hz, 1 H), 7.13 (d,J=7.33 Hz, 1H), 7.16-7.29 (m, 2H), 7.71 (dd, J=8.84, 5.56 Hz, 1H),7.73-7.82 (m, 1H). [M+H] calc'd for C₂₃H₂₄FN₂O₃, 466; found, 466.

Example 88(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylacetamide(Compound 83)

The titled compound 83 was prepared by a procedure analoguous to Example87 except dimethylamine was used. ¹H NMR (400 MHz, METHANOL-d₄) δ 2.74(s, 3H), 2.93 (s, 3H), 3.04 (s, 3H), 3.10-3.24 (m, 1H), 3.35-3.45 (m,1H), 3.91 (s, 3H), 4.69-4.81 (m, 2H), 5.06 (dd, J=9.35, 4.04 Hz, 1H),6.79 (d, J=8.08 Hz, 1H), 7.13 (d, J=7.07 Hz, 1H), 7.16-7.29 (m, 2H),7.70 (dd, J=8.72, 5.68 Hz, 1H), 7.73-7.82 (m, 1H). [M+H] calc'd forC₂₄H₂₆FN₂O₃, 480; found, 480.

Example 89(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetamide(Compound 84)

The titled compound 84 was prepared by a procedure analoguous to Example87 except dimethylamine was used. ¹H NMR (400 MHz, MeOD) δ 2.73 (s, 3H),3.09-3.23 (m, 1 H), 3.34-3.43 (m, 1H), 3.91 (s, 3H), 4.46 (s, 2H),5.01-5.12 (m, 1H), 6.80 (d, J=8.34 Hz, 1 H), 7.12 (d, J=7.07 Hz, 1H),7.16-7.28 (m, 2H), 7.64-7.73 (m, 1H), 7.73-7.82 (m, 1H). [M+H] calc'dfor C₂₂H₂₂FN₇O₃, 452; found, 452.

Example 902-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-14(R)-3-fluoropyrrolidin-1-yl)ethanone(Compound 85)

To a solution of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)aceticacid (0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075 mmol, 28mg), Et₃N (0.125 mmol, 17 μL) and (R)-3-fluoropyrrolidine (0.06 mmol,7.5 mg). The reaction mixture was stirred over night at r.t. and LCMSshows completion of the reaction. Purified by prep LCMS to afford thetitle compound (Compound 85, 13.0 mg, 50%) as light brown solid. ¹H NMR(400 MHz, methanol-d₄) δ ppm 2.05-2.40 (m, 2H) 2.72 (s, 3H) 3.06 (dd,J=16.93, 10.36 Hz, 1H) 3.27-3.38 (m, 1 H) 3.39-3.62 (m, 4H) 3.63-3.78(m, 2H) 3.82 (s, 3H) 4.47-4.67 (m, 2H) 4.87 (dd, J=10.36, 3.03 Hz, 1H)5.11-5.36 (m, 1H) 6.69 (d, J=8.34 Hz, 1H) 6.97 (d, J=7.33 Hz, 1H) 7.06(dd, J=9.35, 2.53 Hz, 1H) 7.13 (t, J=8.34 Hz, 1H) 7.50-7.70 (m, 2H). MS(ES) [M+H] calculated for C₂₆H₂₈F₂N₇O₃, 524.53; found 524.50.

Example 91(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoicacid (Compound 86)

Step A.

To a solution of (S)-3-hydroxydihydrofuran-2(3H)-one (91a, 5 g, 49 mmol)in anhydrous DMF (40 mL) was added imidazole (6.7 g, 98 mmol) andTBDMS-chloride (8.1 g, 54 mmol) and the reaction is stirred for 3 h. Thereaction was diluted with diethyl ether and washed with 1N HCl×3. Theorganic phase was dried over anhydrous sodium sulfate and the solventwas removed in vacuo to yield(S)-3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b) as aclear oil (10.6 g, 49 mmol). ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.15 (s,3H), 0.18 (s, 3H), 0.86-0.99 (m, 9H), 2.23 (dq, J=12.63, 8.67 Hz, 1H),2.46 (dddd, J=12.63, 7.58, 6.57, 3.28 Hz, 1H), 2.84-3.01 (m, 1H), 4.20(td, J=9.16, 6.44 Hz, 1H), 4.33-4.47 (m, 2H).

Step B.

To a solution of(S)-3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b, 6 g, 27.8mmol) in methanol (40 mL) was added potassium carbonate (500 mg, 3.6mmol). The reaction was refluxed overnight. The methanol was removed invacuo and the residue partitioned between ethyl acetate and water. Theorganic phase was washed with H₂O×2 and dried over anhydrous sodiumsulfate. The solvent was removed in vacuo to yield (S)-methyl2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7mmol) as a clear oil. [M+H] calc'd for C₁₁H₂₄O₄Si, 249; found, 249.

Step C.

To a solution of (5)-methyl2-(tert-butyldimethylsilyloxy)-4-hydroxybutanoate (91c, 3.9 g, 15.7mmol) in anhydrous dichloromethane was added triethylamine, DMAP, andmesyl chloride. The reaction was allowed to stir for 1.5 h. The reactionwas quenched with saturated aqueous NH₄Cl. The aqueous phase wasextracted with dicholormethane and the combine organic phases werewashed with brine. The organic layer was dried over anhydrous sodiumsulfate and the solvent removed in vacuo to yield (5)-methyl2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) asa yellow oil. [M+H] calc'd for C₁₂H₂₆O₆SSi, 327; found, 327.

Step D.

To a solution of (S)-methyl2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91d, 4.9 g, 15 mmol) inanhydrous acetone was added sodium iodide (11.5 g, 75 mmol). Thereaction was heated at reflux for 1.5 h. The reaction was quenched withwater and extracted into EtOAc×3. The combined organic phases werewashed with brine then dried over anhydrous sodium sulfate. The solventwas removed in vacuo to yield (S)-methyl2-(tert-butyldimethylsilyloxy)-4-iodobutanoate (91e, 4.33 g, 12 mmol) asa yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ 0.07-0.13 (m, 6H),0.82-0.99 (m, 9H), 2.09-2.32 (m, 2H), 3.17-3.36 (m, 2H), 3.74 (s, 3 H),4.29 (dd, J=8.08, 4.04 Hz, 1H).

Step E.

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (91e, 150 mg, 0.41 mmol) in anhydrous DMF (2 mL) was added cesiumcarbonate (200 mg, 0.62 mmol). The reaction mixture was allowed to stirfor 1 h, at which time (S)-methyl2-(tert-butyldimethylsilyloxy)-4-mesylbutanoate (91f, 220 mg, 0.62 mmol)was added. The reaction was allowed to stir under a nitrogen atmosphereovernight. The reaction was poured onto ice to crash out (S)-methyl4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate(91 g, 244 mg, 0.41 mmol) as a dark yellow precipitate. [M+H] calc'd forC₂₅H₃₅BrFN₅O₄Si, 596; found, 596.

Step F.

To a solution of (S)-methyl4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate(91 g, 244 mg, 0.41 mmol) in DMA was added 6-methoxypyridine-2-boronicacid N-phenyldiethanolamine ester (488 mg, 1.64 mmol), Pd(dppf)₂Cl₂ (66mg, 0.08 mmol), and 2 N Na₂CO₃ (2 mL, 4.1 mmol). The resultant mixturewas degassed with N₂ for 5 min then heated in a sealed tube at 85° C.for 14 h. The reaction was allowed to cool to r.t. and filtered througha pad of Celite topped with anhydrous Na₂SO₄, rinsing with EtOAc andCH₃OH. The filtrate was concentrated to provide a black residue whichwas purified by preparative HPLC eluting with TFA/ACN/H₂O. The fractionswere dried down in vacuo to yield (S)-methyl4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-(tert-butyldimethylsilyloxy)butanoate.This material was directly taken up in dioxane (700 μL) and treated with1:9 TFA:H₂O (1 mL) for 3 h. The solvents were removed in vacuo to yield(S)-methyl4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoate(91h, 15 mg, 0.03 mmol). [M+H] calc'd for C₂₅H₂₇FN₆O₅, 511; found, 511.

Step G.

To a solution of (S)-methyl4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoate(91h, 15 mg, 0.03 mmol) in dioxane (500 μL) was added 1 N LiOH (74 μL,0.08 mmol). The reaction was allowed to stir for 3 h, at which time itwas diluted with 1:1 DMSO:MeOH and purified via preparative HPLC elutingwith TFA/ACN/H₂O. The fractions were dried down in vacuo to yield(S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanoicacid (Compound 86, 7.1 mg, 0.014 mmol) as a yellow oil. ¹H NMR (400 MHz,METHANOL-d₄) δ 1.86-2.08 (m, 1H), 2.18-2.35 (m, 1H), 2.70-2.87 (m, 3H),3.18 (dd, J=16.80, 9.22 Hz, 1H), 3.31-3.44 (m, 1H), 3.84-3.97 (m, 3H),4.10-4.32 (m, 3H), 5.08 (dd, J=9.09, 4.04 Hz, 1H), 6.79 (d, J=8.34 Hz,1H), 7.12 (d, J=7.33 Hz, 1H), 7.14-7.31 (m, 2H), 7.66 (dd, J=8.59, 5.56Hz, 1H), 7.76 (t, J=7.83 Hz, 1H). [M+H] calc'd for C₂₄H₂₅FN₆O₅, 497;found, 497.

Example 923-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H) one (Compound 87)

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (0.3 mmol, 109 mg) in DMF (2.0 mL) was added Cs₂CO₃ (0.45 mmol,146 mg) and 3-bromodihydrofuran-2(3H)-one (0.36 mmol, 33.6 μL). Thereaction mixture was stirred overnight at r.t. and LCMS shows completionof the reaction. The reaction mixture was poured on crushed ice and theresultant solid was filtered and dried to afford3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (105 mg, 78%) as off white solid. MS (ES). [M+H]calculated for C₁₈H₁₈BrPN₅O₃, 450.05; found 450.30.

A mixture of the resultant compound (0.2 mmol, 92 mg),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (0.5 mmol,150 mg), Pd(dppf)₂Cl₂ (0.02 mmol, 16 mg), 2N aq Na₂CO₃ (1.0 mmol, 0.5mL) and DMA (2.0 mL) was degassed with N₂ and heated at 85° C. for 4 h.Cooled to rt, filtered trough celite and purified by prep LCMS to afford2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanoicacid (29 mg, 29%) as brown solid. MS (ES) [M+H] calculated forC₂₄H₂₆PN₆O₅, 497.19; found 497.00.

The resultant compound was dissolved in THF (1.0 ml) and cooled to 0° C.N-methyl morpholine (0.15 mmol, 16.5 μL) and isobutyl chloroformate (0.1mmol, 15.5 μL) was added and the reaction mixture was stirred at ambienttemperature for 2 h. Purified by prep LCMS to afford the title compound3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)one(5 mg, 21%) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.52 (d,J=3.54 Hz, 1H) 2.66 (br. s., 3H) 2.95-3.11 (m, 1H) 3.27 (br. s., 2H)3.79 (s, 3H) 4.19-4.29 (m, 1H) 4.34-4.45 (m, 1H) 4.73-4.91 (m, 2H) 6.67(d, J=8.34 Hz, 1H) 6.94 (d, J=6.57 Hz, 1H) 7.00-7.15 (m, 2H) 7.49-7.66(m, 2H). MS (ES) [M+H] calculated for C₂₄H₂₄FN₆O₄, 479.47; found 479.40.

Example 932-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanamide(Compound 88)

3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)one (14.3 mg, 0.03 mmol) was dissolved in 7N NH₃-MeOH solution andstirred overnight in a sealed tube. The solvent was removed and residuedried to afford the title compound2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxybutanamide(13.2 mg, 89%) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ1.83-2.16 (m, 2H) 2.58 (d, J=6.06 Hz, 3H) 2.85-3.03 (m, 1H) 3.07-3.25(m, 1H) 3.70 (q, J=7.24 Hz, 2H) 3.90 (d, J=11.37 Hz, 3H) 4.54 (td,J=7.83, 5.05 Hz, 1H) 4.97-5.17 (m, 1H) 6.69-6.85 (m, 1H) 7.11 (dd,J=7.71, 2.40 Hz, 1H) 7.14-7.26 (m, 2H) 7.57-7.72 (m, 1H) 7.76 (dd,J=15.03, 6.69 Hz, 1H). MS (ES) [M+H] calculated for C₂₄H₂₇FN₇O₄, 496.50;found 496.40.

Example 942-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(Compound 89) and chiral separation

To a solution of3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(611)-ylidene)aminooxy)dihydrofuran-2(311)-one (310 mg, 0.668 mg) in THF (2 mL) was addedN,N-dimethylamine (2.0M solution in MeOH, 0.86 mL, 1.72 mmol) and thereaction mixture was stirred overnight at r.t. The solvent was removedand purified by LCMS to afford the title compound2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(89, 80 mg, 24%) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) 62.63 (d,J=2.78 Hz, 3H) 2.84-2.99 (m, 1H) 3.01 (d, J=3.28 Hz, 3H) 3.08-3.25 (m,4H) 3.61-3.93 (m, 2H) 4.99 (dddd, J=15.03, 4.86, 2.59, 2.27 Hz, 1H)5.09-5.23 (m, 3H) 5.91 (d, J=9.09 Hz, 1H) 6.98-7.14 (m, 1H) 7.33 (ddd,J=7.89, 4.99, 2.53 Hz, 1H) 7.38-7.48 (m, 1H). MS (ES) [M+H] calculatedfor C₂₀H₂₅BrFN₆O₃, 495.34; found 495.30.

2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(611)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(89) was separated into its enantiomers by supercritical fluidchromatography (SFC) under the following conditions.

-   -   Column: ChiralPak AS-H (250×21 mm, 5 μm)    -   Mobile Phase:        -   A: CO₂ (1)        -   B: i-PrOH    -   Gradient Condition: 25% i-PrOH    -   Run Time: 8 min    -   Flow Rate: 50 mL/min    -   Injection volume: 2000 μL

Example 95 Synthesis of(R)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(Compound 92)

A mixture of(R)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(31 mg, 0.063 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (93 mg, 0.313mmol), Pd(dppf)₂Cl₂ (9.16 mg, 0.013 mmol), 2N aq Na₂CO₃ (0.156 mL, 0.313mmol) and DMA (2.0 mL) was degassed with N₂ and heated at 85° C. for 4h. Cooled to r.t., filtered trough celite and purified by prep LCMS toafford(R)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (92, 14.4 mg, 43.9%) asoff-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 2.08-2.16 (m, 2H) 2.60(s, 3H) 2.98 (s, 3H) 3.02 (d, J=9.85 Hz, 1H) 3.10 (s, 3H) 3.16-3.33 (m,1H) 3.62-3.81 (m, 2H) 3.89 (s, 3H) 4.94 (ddd, J=10.04, 3.98, 0.88 Hz,1H) 5.03 (t, J=6.19 Hz, 1H) 5.27 (br. s., 2H) 5.79 (s, 1H) 6.74 (dd,J=8.34, 0.76 Hz, 1H) 7.01 (dd, J=7.33, 0.76 Hz, 1H) 7.07-7.23 (m, 2H)7.65 (dd, J=8.34, 7.33 Hz, 2H). MS (ES) [M+H] calculated forC₂₆H₃₁FN₂O₄, 524.56; found 524.40.

Example 96(S)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(Compound 93)

A mixture of(S)-2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(26 mg, 0.052 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (78 mg, 0.262mmol), Pd(dppf)₂Cl₂ (7.68 mg, 0.01 mmol), 2N aq Na₂CO₃ (0.131 mL, 0.262mmol) and DMA (2.0 mL) was degassed with N₂ and heated at 85° C. for 4h. Cooled to r.t., filtered trough celite and purified by prep LCMS toafford(S)-2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(93, 10.3 mg, 37%) as off-white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ2.04-2.15 (m, 2H) 2.60 (s, 3H) 2.97 (s, 3H) 3.01-3.07 (m, 1H) 3.13 (s,3H) 3.30 (ddd, J=16.42, 3.79, 1.52 Hz, 1H) 3.70-3.84 (m, 2H) 3.89 (s, 3H) 4.90 (dd, J=10.74, 3.66 Hz, 1H) 5.12 (t, J=6.32 Hz, 1H) 5.26 (br. s.,1H) 5.78 (s, 1H) 6.74 (dd, J=8.34, 0.76 Hz, 1H) 7.02 (dd, J=7.20, 0.88Hz, 1H) 7.11-7.21 (m, 2H) 7.65 (dd, J=8.34, 7.07 Hz, 2H). MS (ES) [M+H]calculated for C₂₆H₃₁FN₇O₄, 524.56; found 524.40.

Example 972-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-1-morpholinobutan-1-one(Compound 94)

To a solution of3-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(611)-ylidene)aminooxy)dihydrofuran-2(311) one (12.0 mg, 0.025 mmol) in THF (1.0 mL) was addedmorpholine (5.52 μL, 0.063 mmol) and the reaction mixture was stirredovernight. Solvent was removed and purified by prep LCMS to afford thetitle compound2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-1-morpholinobutan-1-one(94, 5.7 mg, 40%) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ1.79-2.03 (m, 2H) 2.57 (d, J=7.07 Hz, 3H) 2.99 (ddd, J=16.86, 8.72, 8.53Hz, 1H) 3.10-3.18 (m, 1H) 3.22-3.29 (m, 4H) 3.46-3.55 (m, 4H) 3.57-3.62(m, 2H) 3.81 (d, J=5.81 Hz, 3 H) 4.95 (ddd, J=19.45, 8.84, 4.80 Hz, 1H)5.00-5.06 (m, 1H) 6.70 (dd, J=7.58, 6.06 Hz, 1H) 7.03 (d, J=6.57 Hz, 1H)7.06-7.16 (m, 2H) 7.54 (ddd, J=19.20, 8.34, 5.81 Hz, 1H) 7.67 (td,J=7.83, 4.80 Hz, 1H). MS (ES) [M+H] calculated for C₂₈H₃₃FN₇O₅, 566.59;found 566.50.

Example 982-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-methoxy-N,N-dimethylbutanamide(Compound 95)

To a solution of24Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide(0.03 mmol, 16 mg) in THF (2 mL) was added 50% NaH (0.034 mmol, 1.65 mg)at 0° C. under N₂ atmosphere. The reaction mixture was stirred for 15minutes and dimethyl sulphate (4.08 μL, 0.043 mmol) was added. Thereaction mixture was stirred at r.t. for 3 h. Quenched with MeOH (1 mL)and purified by LCMS to afford the title compound2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-methoxy-N,N-dimethylbutanamide(95, 3.6 mg, 25%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.81-2.06 (m, 2H) 2.47 (s, 3H) 2.70-2.80 (m, 1H) 2.83 (d, J=10.61 Hz,3H) 3.05 (d, J=7.58 Hz, 3H) 3.07-3.17 (m, 1H) 3.20 (d, J=4.80 Hz, 3H)3.31-3.39 (m, 2H) 3.40-3.49 (m, 2H) 3.87 (d, J=3.79 Hz, 3H) 4.80-4.93(m, 1H) 5.06-5.22 (m, 1H) 6.83-6.90 (m, 1H) 7.20 (d, J=8.84 Hz, 1H)7.23-7.32 (m, 2H) 7.44 (ddd, J=14.34, 8.91, 5.81 Hz, 1H) 7.85 (td,J=7.83, 3.28 Hz, 1H). MS (ES) [M+H] calculated for C₂₇H₃₃PN₇O₄, 538.58;found 538.40.

Example 99 Synthesis of2-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-N—((S)-2,3-dihydroxypropyl)-N-methylacetamide(Compound 96)

¹H NMR (400 MHz, METHANOL-d₄) δ 2.57 (d, J=5.31 Hz, 3H), 2.89-3.21 (m, 5H), 3.34-3.65 (m, 4H), 3.75-3.88 (m, 1H), 3.89 (s, 3H), 4.55-4.77 (m,4H), 5.01 (dt, J=9.16, 4.64 Hz, 1H), 6.77 (d, J=8.34 Hz, 1H), 7.12 (d,J=7.33 Hz, 1H), 7.13-7.25 (m, 2H), 7.67 (dd, J=8.21, 5.68 Hz, 1H), 7.75(t, J=7.83 Hz, 1H). [M+H] calc'd for C₂₆H₃₀FN₇O₅, 540; found, 540.

Example 100 Synthesis of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-cyclopropylacetamide(Compound 97)

The titled compound 97 was prepared by a procedure analoguous to Example87 except cyclopropanamine was used ¹H NMR (400 MHz, MeOD) δ 0.43-0.53(m, 2H), 0.68-0.79 (m, 2H), 2.67 (dt, J=7.33, 3.41 Hz, 1H), 2.71 (s,3H), 3.09-3.21 (m, 1H), 3.37-3.52 (m, 1H), 3.91 (s, 3H), 4.43 (s, 2H),5.06 (dd, J=9.35, 4.29 Hz, 1H), 6.80 (d, J=8.34 Hz, 1H), 7.13 (d, J=7.07Hz, 1H), 7.15-7.29 (m, 2H), 7.69 (dd, J=8.84, 5.56 Hz, 1H), 7.72-7.83(m, 1H). [M+H] calc'd for C₂₅H₂₆FN₇O₃, 492; found, 492.

Example 101 Synthesis of(R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide(Compound 98)

A solution of(R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)butanoicacid (101a, 26 mg, 0.054 mmol) in anhydrous THF was chilled in an icebath and N-methylmorpholine (9 μL, 0.081 mmol) and isobutylchloroformate (7.7 piL, 0.060 mmol) were added sequentially. The mixturewas stirred under an N₂ atmosphere for 20 min. A 33 wt % solution ofdimethylamine in methanol (54 μL, 0.11 mmol) was added to the reactionwhich was subsequently allowed to warm to room temperature with stirringovernight. The THF was removed in vacuo and the residue was partitionedbetween ethyl acetate and water. The organic phase was washed with H₂O×2and dried over anhydrous Na₂SO₄. The ethyl acetate was removed in vacuoand the residue was purified via preparative HPLC to yield(R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide(98, 6.4 mg, 0.0126 mmol).

¹H NMR (400 MHz, MeOD) δ 1.91-2.05 (m, 2H), 2.46 (t, J=7.33 Hz, 2H),2.70 (s, 3H), 2.87 (s, 3H), 3.00 (s, 3H), 3.02-3.16 (m, 1H), 3.25 (dd,J=16.55, 4.67 Hz, 1H), 3.91 (s, 3H), 4.00-4.12 (m, 2H), 5.05 (dd,J=8.59, 4.55 Hz, 1H), 6.79 (d, J=8.34 Hz, 1H), 7.12 (d, J=7.33 Hz, 1H),7.15-7.25 (m, 2H), 7.59 (dd, J=8.46, 5.68 Hz, 1H), 7.71-7.82 (m, 1H).[M+H] calc'd for C₂₆H₃₀FN₇O₃, 508; found, 508.

Example 102 Synthesis of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(2-hydroxyethyl)-N-methylacetamide(Compound 99)

To a solution of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)aceticacid (102a, 43 mg, 0.095 mmol) in anhydrous DMF (1 mL) was added2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(72 mg, 0.19 mmol), triethylamine (53 piL, 0.39 mmol), and finally2-(methylamino)ethanol (102b, 16 μL, 0.19 mmol). The reaction wasallowed to stir under a nitrogen atmosphere overnight. The reactionmixture was diluted with 1:1 DMSO:MeOH and purified via preparative HPLCeluting with NH₄HCO₃/ACN/H₂O. The titled compound (Compound 99, 11 mg,0.022 mmol) was crashed out from the HPLC fractions as a white solid. ¹HNMR (400 MHz, METHANOL-d₄) δ 2.57 (d, J=4.04 Hz, 3H), 2.86-3.21 (m, 5H),3.44-3.55 (m, 2H), 3.66-3.73 (m, 2H), 3.89 (s, 3H), 4.69-4.82 (m, 2H),5.01 (dt, J=9.09, 4.29 Hz, 1H), 6.77 (d, J=8.34 Hz, 1H), 7.12 (d, J=7.33Hz, 1H), 7.14-7.24 (m, 2H), 7.60-7.70 (m, 1H), 7.70-7.80 (m, 1H). [M+H]calc'd for C₂₅H₂₈FN₂O₄, 510; found, 510.

Example 103 Synthesis of24(Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypyrrolidin-1-ypethanone(Compound 100)

The titled compound 100 was prepared by a procedure analoguous toExample 102 except (S)-pyrrolidin-3-ol was used. ¹H NMR (400 MHz,METHANOL-d₄) δ 1.82-2.13 (m, 2 H), 2.57 (d, J=3.03 Hz, 3H), 2.95 (ddd,J=16.23, 8.91, 3.92 Hz, 1H), 3.09-3.22 (m, 2H), 3.38-3.54 (m, 2H),3.54-3.74 (m, 2H), 3.90 (s, 3H), 4.41 (d, J=9.35 Hz, 1H), 4.55-4.73 (m,2H), 4.96-5.08 (m, 1H), 6.78 (d, J=8.34 Hz, 1H), 7.12 (d, J=7.07 Hz,1H), 7.13-7.24 (m, 2H), 7.64 (dt, J=8.53, 5.84 Hz, 1H), 7.75 (t, J=7.83Hz, 1H). [M+H] calc'd for C₂₆H₂₈FN₇O₄, 522; found, 522.

Example 104 Synthesis of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-diethylacetamide(Compound 101)

The titled compound 101 was prepared by a procedure analoguous toExample 102. ¹H NMR (400 MHz, METHANOL-d₄) δ 1.12 (t, J=7.07 Hz, 3H),1.15-1.26 (m, 3H), 2.71 (s, 3H), 3.17 (dd, J=16.80, 9.47 Hz, 1H),3.32-3.46 (m, 5H), 3.89 (s, 3H), 4.65-4.81 (m, 2H), 5.05 (dd, J=9.47,4.17 Hz, 1H), 6.79 (d, J=8.34 Hz, 1H), 7.13 (d, J=7.33 Hz, 1H),7.15-7.29 (m, 2H), 7.70 (dd, J=8.59, 5.56 Hz, 1H), 7.72-7.83 (m, 1H).[M+H] calc'd for C₂₆H₃₀FN₂O₃, 508; found, 508.

Example 105 Synthesis of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone(Compound 102)

A.(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (105a)

A mixture of(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione(31I, 366 mg, 1.0 mmol), O-(tert-butyldimethylsilyl)hydroxylamine (588mg, 4.0 mmol), Hg(OAC)₂ (640 mg, 2.0 mmol) and toluene (5 mL) was heatedat 100° C. for 2 h. The mixture was cooled to r.t. and filtered throughcelite. Filtrate concentrated and the resulting oily residue wastriturated with dry methanol to afford a pale yellow solid. Filtered anddried to afford((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (105a, 384 mg, 80%) as a pale yellowsolid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (s, 3H), 0.23 (s, 3H)0.97 (s, 9H) 2.70 (s, 3H) 2.91 (dd, J=16.42, 8.08 Hz, 1H) 3.19 (ddd,J=16.36, 4.86, 1.26 Hz, 1H) 4.99 (ddd, J=7.77, 5.12, 2.02 Hz, 1H) 7.05(td, J=8.27, 2.65 Hz, 1H) 7.33 (dd, J=8.08, 2.78 Hz, 1H) 7.39 (dd,J=8.72, 5.94 Hz, 1 H). MS (ES) [M+H] calculated for C₂₀H₂₈BrFN₅OSi,480.12; found 480.30.

B. (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (105b)

To a solution of((R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-tert-butyldimethylsilyloxime (105a, 384 mg, 0.8 mmol) in dioxane (2mL) was added 1:9 TFA-H₂O and the reaction mixture stirred at rt for 2h. The resultant sold was filtered and washed with dioxane. Theresultant solid was dried to afford(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (105b, 206 mg, 70%) as a paleyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.56 (s, 3H) 2.83 (dd,J=15.92, 4.55 Hz, 1H) 3.17 (dd, J=16.04, 5.94 Hz, 1H) 4.90 (q, J=4.97Hz, 1H) 7.20 (d, J=1.52 Hz, 1H) 7.21-7.23 (m, 1H) 7.57 (ddd, J=8.34,1.64, 1.39 Hz, 1 H) 9.82 (s, 1H). MS (ES) [M+H] calculated forC₁₄H₁₄BrFN₅O, 366.03; found 366.20.

C. (R,Z)-methyl2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetate(105c)

To a solution of(R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (105c, 150 mg, 0.4 mmol) in dryDMF (1 mL) was added CsCO₃ (195 mg, 0.6 mmol) and the reaction mixturestirred at ambient temperature for 30 minutes. Then methyl2-bromoacetate (45 μL, 0.48 mmol) was added and the reaction mixturestirred for overnight. LCMS shows completion of the starting material.The reaction mixture was poured on crushed ice and the resultant soldwas filtered and washed with cold water. The resultant solid was driedto afford (R,Z)-methyl2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetate(105c, 172 mg, 99%) as a light brown solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 2.66 (s, 3H) 3.12-3.18 (m, 1H) 3.24-3.32 (m, 1H)3.71 (s, 3H) 4.57 (s, 2H) 4.96 (ddd, J=8.40, 4.48, 1.77 Hz, 1 H) 7.01(td, J=8.27, 2.65 Hz, 1H) 7.23-7.29 (m, 1H) 7.39 (dd, J=8.84, 5.81 Hz,0H). MS (ES) [M+H] calculated for C₁₂H₁₈BrFN₅O₃, 438.05; found 438.00.

D.(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)aceticacid (105d)

A mixture of (R,Z)-methyl2-(2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)acetate(105c, 175 mg, 0.4 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (298 mg, 1,0mmol), Pd(dppf)₂Cl₂ (32.5 mg, 0.04 mmol), 2N Na₂CO₃ (1.0 mL, 2.0 mmol)in DMA (3 mL) was degassed with N₂ and heated at 85° C. for over night.The reaction mixture was cooled to ambient temperature, diluted withethyl acetate and filtered through celite. The filtrate was concentratedto afford brown oil which was purified by preparative LCMS to afford(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)aceticacid (105d, 56 mg, 31%) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 2.79 (s, 3H) 3.16 (dd, J=17.05, 10.48 Hz, 1H) 3.45 (dd, J=17.05,3.92 Hz, 1H) 3.88 (s, 3H) 4.59 (d, J=3.03 Hz, 2H) 4.96 (dd, J=10.36,3.79 Hz, 1H) 5.90 (brs, 1 H) 6.76 (d, J=8.34 Hz, 1H) 7.02 (d, J=6.82 Hz,1H) 7.14 (dd, J=9.09, 2.78 Hz, 1H) 7.19 (td, J=8.34, 2.78 Hz, 1H) 7.62(dd, J=8.59, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS (ES) [M+H]calculated for C₂₂H₂₂FN₆O₄, 453.16; found 453.30.

E.(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone(Compound 102)

To a solution of(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)aceticacid (105d, 0.05 mmol, 22.6 mg) in DMF (0.5 mL) was added HBTU (0.075mmol, 28 mg), Et₃N (0.125 mmol, 17 μL) and morpholine (0.1 mmol, 8.3μL). The reaction mixture was stirred over night at r.t. and LCMS showscompletion of the reaction. Purified by prep LCMS to afford the titlecompound(R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-morpholinoethanone(102, 5.7 mg, 22%) as off white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 2.83 (s, 3H) 3.15 (dd, J=17.31, 10.23 Hz, 2H) 3.43-3.51 (m, 2H) 3.63(d, J=5.31 Hz, 2H) 3.65-3.71 (m, 4H) 3.89 (s, 3H) 4.71 (s, 2H) 4.97 (dd,J=10.36, 3.79 Hz, 1H) 5.96 (br. s., 1H) 6.77 (d, J=8.34 Hz, 1H) 7.03 (d,J=7.07 Hz, 1H) 7.14 (dd, J=9.35, 2.78 Hz, 1H) 7.19 (td, J=8.40, 2.65 Hz,1H) 7.63 (dd, J=8.84, 5.56 Hz, 1H) 7.68 (dd, J=8.34, 7.33 Hz, 1H). MS(ES) [M+H] calculated for C₂₆H₂₈FN₇O₄, 522.22; found 522.00.

The reaction schemes ddisclosed in the Example above was used to preparethe compounds listed in the following table:

Compound M + H No. Structure & Name MW (observed) 103

539.6 540 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-bis(2- hydroxyethyl)acetamide 104

539.6 567.6 568 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-N,N-bis(2- hydroxypropyl)acetamide105

491.5 492 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(azetidin-1- yl)ethanone 106

505.5 506 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrrolidin-1- yl)ethanone 107

535.6 536 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone 108

535.6 536 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-hydroxypiperidin-1- yl)ethanone 109

570.6 571 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-((6-methylpyridin-2-yl)methyl)acetamide 110

567.6 568 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-bis(2- methoxyethyl)acetamide 111

522.5 523 (R,Z)-N-(2-amino-2-oxoethyl)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)- N-methylacetamide112

535.6 536 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethanone 113

523.6 524 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(2-methoxyethyl)-N- methylacetamide 114

521.5 522 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydroxypyrrolidin-1- yl)ethanone 115

535.6 536 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-hydroxypiperidin-1- yl)ethanone 116

521.5 522 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypyrrolidin-1- yl)ethanone 117

535.6 536 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-hydroxypiperidin-1- yl)ethanone 118

507.5 508 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3-hydroxyazetidin-1- yl)ethanone 119

541.5 542 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3,3-difluoropyrrolidin-1- yl)ethanone 120

523.5 524 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((R)-3-fluoropyrrolidin-1- yl)ethanone 121

523.5 524 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-((S)-3-fluoropyrrolidin-1- yl)ethanone 122

549.6 550 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4-methoxypiperidin-1- yl)ethanone 123

527.5 528 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3,3-difluoroazetidin-1- yl)ethanone 124

563.6 564 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(methoxymethyl)piperidin- 1-yl)ethanone 125

536.6 537 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-(2-(methylamino)-2- oxoethyl)acetamide126

546.6 547 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-(isoxazol-3-ylmethyl)-N- methylacetamide 127

562.6 563 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-(thiazol-4- ylmethyl)acetamide 128

557.6 558 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(pyrazin-2-yl)ethanone 129

562.6 563 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(dimethylamino)piperidin- 1-yl)ethanone 130

574.6 575 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(2-methyltetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)ethanone 131

559.6 560 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)acetamide 132

571.6 572 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(2-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone 133

535.6 536 2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-1-(3-(hydroxymethyl)pyrrolidin- 1-yl)ethanone134

574.6 575 2-(2-((Z)-((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)acetyl)hexahydropyrrolo[1,2- a]pyrazin-6(7H)-one135

521.5 522 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(3-methoxyazetidin-1- yl)ethanone 136

555.6 556 (R,Z)-2-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-1-(4,4-difluoropiperidin-1- yl)ethanone

Example 106 Alternative synthesis of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (Compound 61)

Step A. Synthesis of(R)-5-(1H-benzo[d][1,2,3]triazol-1-yl)-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-2-amine(Compound 106c)

In a 2-neck round-bottomed flask, under a blanket of nitrogen was added(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one(106a, 1.00 g, 2.85 mmol), 1H-benzo[d][1,2,3]triazole (106b, 0.678 g,5.70 mmol) and anhydrous acetonitrile (14 mL). Phosphoryl trichloride(0.796 mL, 8.54 mmol) was added slowly to the mixture and the reactionwas heated in 75° C. oil bath for 18 hours. By LC/MS about 7-10% ofcompound 1 remained unreacted. The reaction mixture was concentrated,then diluted with 80 mL of ethyl acetate and the resulting mixture wasadded slowly to 40 mL of saturated sodium bicarbonate. The layers werepartitioned. The aqueous layer was washed one more time with 40 mL ofethyl acetate. The organic layers combined, washed with brine, driedover sodium sulfate, and concentrated to a yellow-light brown solid,1.72 g, contained about 0.37 g of excess benzotriazole. The crudematerial was taken on to the next step without purification. MS (ES)[M+H] calc'd for C₂₀H₁₅BrFN₇, 452; found, 452.3-454.3. ¹H NMR (400 MHz,CHLOROFORM-d) δ 1.96 (s, 3H), 2.74 (dd, J=16.42, 14.91 Hz, 1H), 3.13(dd, J=16.55, 4.17 Hz, 1H), 5.20 (dd, J=14.91, 4.04 Hz, 1H), 5.69 (s,2H), 7.03-7.12 (m, 1H), 7.38 (dd, J=8.21, 2.65 Hz, 1H), 7.47-7.52 (m,1H), 7.56-7.63 (m, 1H), 7.74 (dd, J=8.84, 6.06 Hz, 1H), 8.16 (d, J=9.35Hz, 2H).

Step B. Synthesis of(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine(Compound 106e)

(R)-5-(1H-benzo[d][1,2,3]triazol-1-yl)-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-2-amine(1.13 g, 2.50 mmol) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.322g, 2.75 mmol) were combined in 15 mL of acetonitrile. Then acetic acid(0.858 mL, 15.0 mmol) was added and the reaction mixture was stirred atroom temperature for 18 h. Next day, the reaction was complete and itwas concentrated in vacuo and then purified by flash columnchromatography, SiO₂, gradient 30-100% ethyl acetate/hexane. Obtained0.838 g of compound 5, 74.5% yield. MS (ES) [M+H] calc'd forC₁₉H₂₁BrFN₅O₂, 450; found, 450.3-452.3. ¹H NMR (400 MHz, CHLOROFORM-d) δ1.45-1.97 (m, 6H), 2.72 (s, 3H), 2.91 (ddd, J=16.17, 10.86, 7.83 Hz,1H), 3.05-3.26 (m, 1H), 3.58-3.71 (m, 1H), 3.86-4.08 (m, 1H), 4.92-5.06(m, 1H), 5.25 (dd, J=5.81, 2.27 Hz, 1H), 5.63 (d, J=4.04 Hz, 2H),5.79-5.88 (d, J=36 Hz, 1H), 6.93-7.11 (m, J=16.07, 8.19, 8.19, 2.65 Hz,1H), 7.28-7.34 (m, 1H), 7.35-7.44 (ddd, J=36 Hz, 1H).

Step C. Synthesis of(7R)-7-(4-fluoro-2-(6-methoxypyridin-2-yOphenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine(Compound 106g)

(7R)-7-(2-bromo-4-fluorophenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine(0.838 g, 1.86 mmol),2-(6-methoxypyridin-2-yl)-6-phenyl-1,3,6,2-dioxazaborocane (1.33 g, 4.47mmol), sodium carbonate 2M solution (3.72 mL, 7.44 mmol) were combinedin N,N-Dimethylacetamide (12 mL) and then the mixture was purged withnitrogen for 5 minutes. 1,1’-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.136 g, 0.186 mmol) was thenadded and the reaction was heated in 85° C. oil bath overnight. Nextday, the reaction was diluted with ethyl acetate 80 mL, washed withbrine (80 mL), dried over sodium sulfate, and concentrated to a crudeproduct which was then purified by flash column chromatography, SiO₂,gradient 20-100% ethyl acetate/hexane to give a white solid, 1.11 g ofproduct, contaminated with the impurity of mass 182 (byproduct from theboronic ester, compound 6). MS (ES) [M+H] calc'd for C₂₅H₂₂FN₆O₃, 479;found, 479.4.

Step D. Synthesis of(R,Z)-2-amino-7-(4-fluoro-2(6-methoxypyridine-2-Aphenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneoxime (Compound 61)

(7R)-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-5-(tetrahydro-2H-pyran-2-yloxyamino)-7,8-dihydropyrido[4,3-d]pyrimidin-2-amine(0.891 g, 1.86 mmol) was dissolved in 10 mL of dioxane. 4M of HCl indioxane (1.86 mL, 7.45 mmol) was then added slowly to the above stirredsolution. After all the HCl was added, a yellow solid was formed at thebottom of the reaction flask. The deprotection was allowed to go for 30minutes, then the supernatant was decanted. Dichloromethane was added towash the solid, then it was decanted. This process was repeated a fewtimes. No product was found in the dioxane and dichloromethane washes.The solid product was then purified on flash column chromatography,SiO₂, gradient 2-15% methanol/chloroform to give 0.404 g of product,63.5% yield over 2 steps. MS (ES) [M+H] calc'd for C₂₀H₁₉PN₆O₂, 395;found, 395.3. ¹H NMR (400 MHz, METHANOL-d₄) δ 2.60 (s, 3 H), 3.09-3.19(m, 1H), 3.29-3.34 (m, 1H), 3.91 (s, 3H), 5.45 (br. s., 1H), 6.82 (d,J=8.34 Hz, 1H), 7.16 (d, J=6.57 Hz, 1H), 7.19-7.30 (m, 2H), 7.55 (dd,J=8.59, 5.56 Hz, 1H), 7.79 (dd, J=8.34, 7.33 Hz, 1H).

Example 107 Preparation of(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO—(S)-3,4-dihydroxybutyl oxime benzoate Form A

(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-3,4-dihydroxybutyl oxime (Compound 37, 20 mg, a white powder) wasweighed in a reaction vessel equipped with a magnetic stirring bar.Chloroform (5 mL) and benzoic acid in 1,4-dioxane (340 mL, 0.124 mol/L)were added, and the reaction mixture was cooled at 5° C. The solvent wasevaporated with a gentle stream of nitrogen, providing a paste.

Acetone (2.5 mL) was added to the residue. The mixture was sonicated atroom temperature until a solution was obtained. Heptane (1 mL) was addedand the reaction mixture was cooled at 5° C. The solvent was evaporatedwith a gentle stream of nitrogen yielding a solid.

The residual solid was characterized by powder X-ray diffraction,differential scanning calorimetry (DSC) and thermogravimetry. FIG. 2shows the powder X-ray diffraction diffractogram, which containsdistinct lines characteristic of a crystalline product. FIG. 3 shows anDSC thermogram which shows an endotherm that starts at 128° C. The solidpossesses a melting point of 128° C.

In addition, the above reaction schemes and variations thereof can beused to prepare the following compounds. It is understood thatrecitation of a compound is intended to encompass all of the differentpossible stereoisomers.

Example A Biological Assays

1. Enzyme Binding (Fluorescence Polarization) Assay for HSP90Inhibitors.

a. Preparation of HSP90a Protein

This example describes cloning, expression and purification of a proteincomprising the N-terminal domain of HSP90a. It should be noted that avariety of other expression systems and hosts are also suitable for theexpression of such protein, as would be readily appreciated by one ofskill in the art.

The sequence of human wild-type HSP90a is well known in the art; see,Chen B. et al. Genomics 2005.86:627-637. The gene encoding HSP90a can beisolated from RNA, cDNA or cDNA libraries. In this case, the geneencoding residues 9-236 of image clone 5270926 of HSP90α (ATCC) wasisolated. This portion of the gene encoding a section of human HSP90athat includes the N-terminal nucleotide binding domain of human HSP90awas cloned into pET28a vector (Novagen). The DNA sequence of the vectoris shown in SEQ ID NO: 1. Expression from this vector produced a proteinconsisting of the recombinant N-terminal nucleotide binding domain ofHSP90a with a cleavable 6′-histidine tag and a cleavage site at theN-terminus The amino acid sequence of this recombinant protein is shownin SEQ ID NO: 2.

Recombinant human N-terminal truncated His₆-HSP90a was expressed in E.coli (BL21) cells with IPTG induction. Cell paste from 24×60 mL tubes(grown in a multi-tube airlift fermentor) was lysed using an automatedsample lyser. Briefly, the pellet in each tube was suspended in 21 mL oflysis buffer consisting of 50 mM Tris pH 7.9, 50 mM NaCl, 1 mM MgCl₂,0.6 g/L Lysozyme (Sigma), 100 μL/L Benzonase (Novagen). After lysis,buffer was added; the tubes were sonicated for 75 seconds, and thenincubated for 20 minutes. After incubation, 5 M NaCl was added to bringthe final salt concentration to 400 mM. The tubes were sonicated for 50seconds and then centrifuged at 3400 rpm for 50 min. The supernatantswere pooled and 4 ml of ProBond Ni resin (Invitrogen) was added. Afterat least 30 minutes, the resin was spun down, washed with 25 mM Tris pH7.6, 400 mM NaCl, 20 mM imidazole, poured into a column and washed with10 column volumes of the same buffer. The protein was eluted from thecolumn using 3 column volumes of 25 mM Tris pH 7.6, 400 mM NaCl, 400 mMimidazole. The eluate was loaded onto a Supedex 200 column (GEHealthcare) equilibrated with 25 mM Tris pH 7.6, 250 mM NaCl, 0.25 mMTCEP, 1 mM EDTA and peak fractions were pooled and concentrated to ˜6mg/mL using 10 kDA MWCO centrifugal concentrators (Millipore). Aliquotswere flash frozen in liquid nitrogen and stored at −80° C. Allpurification was done at 4° C.

b. Preparation of the Fluorescence Polarization Probe.

A fluorescein labeled small molecule was designed and synthesized as aprobe (TSD-FP probe) for the determination of the binding affinity ofthe test compound to HSP90 proteins. The synthesis of the smallmolecule,(S,E)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-2-aminoethyl oxime (Compound 24) was described in Examples 24 and 25above. The TSD-FP probe was prepared according to the followingprocedure:

To a 4 mL vial containing a solution of Compound 24 (5 mg, 0.00908 mmol,1.0 eq.) in dichloromethane (0.6 mL) and triethylamine (6.3 μL, 0.0454mmol) was added a solution of(5-((2,5-dioxopyrrolidin-1-yloxy)carbonyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid (5-FAM, 4.7 mg, 0.01 mmol, 1.1 eq.) in dichloromethane (0.4 mL);the mixture was stirred at room temperature overnight. When the reactionwas completed, as determined by LC/MS, the reaction mixture was dilutedwith MeOH and purified directly by preparative HPLC to give the TSD-FPprobe as a white solid (6.8 mg, 75%). ESI-MS: m/z 795.4 (M+H)⁺.

c. Assaying the In Vitro Enzymatic Activity of HSP90 Inhibitors.

The inhibitory effect of the compounds of the invention against HSP90awas determined by fluorescence polarization assay. The assay was run ina black 384-well-plate and in an assay buffer comprising 25 mM Hepes pH7.3, 150 mM NaCl, 0.1 mM EDTA, 0.01% Brij35, 1 mM DTT.

To each test well, an aliquot of buffer, 2 μl of test compound in 10%DMSO, 4 μl of 6.25 nM of TSD FP probe, 4 μl of 12.5 nM of purifiedHSP90a protein were added. For positive control, 1 μM geldanamycin (GM)was used instead of the test compound (GM is a natural benzoquinoneansamycin that is known to bind to the N-terminal ATP-binding pocket ofHSP90 and inhibits ATP binding and ATP-dependent chaperone activities).For negative control, no inhibitor was added. The assay mixtures wereincubated at room temperature for 60 min and overnight (960 min) Thefluorescence intensity of the assay mixtures (both 60 min and overnightincubation) was obtained using an Analyst HT (Molecular Devices) withexcitation wavelength of 485 nm and emission wavelength of 535 nm.

d. Calculation of IC₅₀ Values

IC₅₀ value may be calculated by non-linear curve fitting of the compoundconcentrations and FP signal to the standard IC₅₀ equation. See, J. Kimet al. “Development of a Fluorescence Polarization Assay for theMolecular Chaperone Hsp90” J. Biomolecular Screening 2004.9(5).

The percent inhibition of HSP90 at a given compound concentration isdefined as:

100%×[1−(FPcompound/FPblank)]

where FPcompound is the observed polarized fluorescence at a givenconcentration of test compound and FPblank is the observed polarizedfluorescence in the presence of vehicle alone.

The pIC₅₀ value (negative log of the molar concentration of the compoundthat produces 50% inhibition) of a test compound is calculated bynon-linear least squares curve fitting of the equation:

Percent Inhibition=100%/(1+(10−pIC₅₀/10 log[I]))

to percent inhibition versus compound concentration. The 50% inhibitoryconcentration (IC₅₀) of a test compound is calculated by raising 10 tothe negative pIC₅₀ (10-pIC₅₀).

As reference, known HSP90 inhibitors, geldanamycin (GM) and 17alkylamino, 17-demethoxygeldanamycin (17-AAG), were assay and theresults summarized in Table 1. It is noted that these two inhibitorsshowed a time dependence behavior of HSP90 binding which are not common,among the small molecule inhibitors of the invention.

TABLE 1 IC₅₀ Values of Known HSP90 Inhibitors Standard IC₅₀ (nM) afterIC₅₀ (nM) after Compounds 1 hour incubation overnight incubationGeldanamycin 90 10 17-AAG 400 110

2. Cellular Viability Assay

BT-474, HT-29, K-562 and MKN-45 tumor cell lines were maintainedaccording to the suppliers (American Type Culture Collection, Rockville,Md. or Human Science Research Resources Bank, Osaka, Japan). Cells wereseeded in 96-well tissue culture microplates at 5,000-25,000 cells perwell and cultured for 24 hours prior to addition of compounds or DMSO(dimethylsulfoxide) vehicle. A sample where the cells were only treatedwith DMSO was used a negative control and A sample where the cells weretreated with 17-AAG was used a positive control. After 72 hours of testcompound treatment, the conversion of tetrazolium salt MTS (Promega,Madison, Wis.) by metabolically active cells was determined throughmeasuring the OD_(490 nm) with a Spectramax microplate reader (MolecularDevices, San Diego, Calif.). To generate concentration-response curves,cells were treated in duplicate with a range of serial compounddilutions (final DMSO concentration was 0.5%). The percentage of viablecells per well was determined by correcting for background andnormalizing against DMSO-treated cells. EC₅₀ values for inhibition ofcell viability were calculated using XLfit4 Microsoft Excelcurve-fitting software.

3. HSP7013 Induction Assay

The HSP7013/13-galactosidase reporter vector was purchased fromStressgen Bioreagents Corporation (Victoria, BC Canada). This vector wastransiently transfected into 2 million HeLa cells per 10 cm² dishaccording to the protocol provided by Stressgen using the lipid basedtransfection reagent HeLaMONSTER (Mirus Bio Corporation, Madison, Wis.).Cells were subsequently plated in 96 well plates at 20,000 cells/welland after 24 hours of recovery dosed with test compounds for 10 hours.To generate concentration-response curves, cells were treated induplicate with a range of serial compound dilutions (final DMSOconcentration was 0.5%). To measure (3-galactosidase activity, lysateswere prepared using the Galacto-Star System (Applied Biosystems,Bedford, Mass.). Total non-infrared luminescence was read on an EnVisionplate reader (Perkin Elmer, Turku, Finland). EC₅₀ values forHSP7013/13-galactosidase induction were calculated using XLfit4Microsoft Excel curve-fitting software. A sample where the cells weretreated with DMSO only was used a negative control, and a sample of17-AAG was used as a positive control.

4. Western Blotting of the HSP90 Client Protein HER-2

1 million SKOV3 cells (American Type Culture Collection, Rockville, Md.)were seeded in 35 mm² wells in McCoy's 5A medium containing 10% fetalbovine serum. 24 hours after seeding, cells were treated with compoundsserially diluted 2.5-fold in DMSO (final DMSO concentration was 0.5%).After 16 hours of test compound incubation, whole cell lysates wereprepared by lysing cells in 62.5 mM Tris-HCl, pH 7, 1% SDS, 10%glycerol. Proteins were resolved by SDS-PAGE and transferred to PVDFmembranes. Membranes were probed with the appropriate primary antibodiesfollowed by incubation with secondary IRDye 680- or 800CW-conjugatedantibodies (Li-Cor, Lincoln, Nebr.). HER-2/ERBB2 was analyzed usingmonoclonal antibodies (Cell Signaling Technologies, Danvers, Mass.).Total HSP70 levels were also analyzed using a mouse monoclonal antibody(Stressgen, Ann Arbor, Mich.). PCNA was used as a control for proteinloading and was detected by a monoclonal antibody (Calbiochem, SanDiego, Calif.). Blots were scanned on the Odyssey (Li-Cor, Lincoln,Nebr.) and signals corresponding to PCNA, HER-2/ERBB2, were quantifiedusing Li-Cor software. Loss of total HER-2/ERBB2 protein EC₅₀s wereobtained by curve-fitting the ratios of total HER-2/ERBB2 signal overPCNA protein signal using XLfit4 Microsoft Excel curve-fitting software.

Example B In vitro HSP90 Binding Affinity of Compound of the Invention

The enzyme activities of the compounds of the present invention againstHSP90 were determined using the method disclosed Example A-1. Thecompounds of the invention are inhibitors of HSP90; the IC₅₀ values ofthe exemplified compounds are typically less than 1 nM and moretypically less than 100 nM. The IC₅₀ values of selected compounds arereported in Table 2.

TABLE 2 IC₅₀ of Exemplified Compounds Against HSP90 Binding AffinityCompound No IC₅₀(nM) 33 4 35 13 37 6 40 10 45 10 58 5 59 8 61 3 65 10 7510 78 4 79 6 83 8 85 4 93 8 96 13 99 8

1.-115. (canceled)
 116. The compound according to any one of claims188-192, wherein the compound is present as a mixture of stereoisomers.117. The compound according to any one of claims 188-192, wherein thecompound is present as a single stereoisomer.
 118. A pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of claims 188-192 and a pharmaceutically acceptable excipient.119.-187. (canceled)
 188. The compound(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime or a pharmaceutically acceptable saltthereof.
 189. The compound(R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-2,3-dihydroxypropyl oxime or a pharmaceutically acceptable saltthereof.
 190. The compound(R,Z)-2-Amino-7-(3′-(cyclopropylsulfonyl)-5-fluorobiphenyl-2-yl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-oneO-(S)-2,3-dihydroxypropyl oxime or a pharmaceutically acceptable saltthereof.
 191. The compound(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(R)-2,3-dihydroxypropyl oxime or a pharmaceutically acceptable saltthereof.
 192. The compound(E)-2-Amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-oneO-(S)-2,3-dihydroxypropyl oxime or a pharmaceutically acceptable saltthereof.